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We spoke with Dr. Rafael Malagoli, CEO of Bioma Genetics Laboratory in São Paulo, Brazil, about a remarkable case that highlights the importance of persistence and comprehensive genetic analysis in hereditary breast cancer care. Using SOPHiA DDM™ hereditary cancer and exome solutions, Rafael and his team were able to uncover a crucial genetic finding that changed a family’s future.
Watch the interview:
Initial investigation
A 42-year-old Black woman from Rio de Janeiro was diagnosed with an aggressive micropapillary, grade 3 triple-negative breast cancer. Given her young age and strong family history — her mother and maternal grandmother had both been affected by breast cancer — Bioma Genetics performed genetic analysis using a SOPHiA DDM™ Custom Hereditary Cancer Solution, covering 144 genes.
To the team’s surprise, no pathogenic variants were detected in the initial investigation. However, given the patient's clinical presentation and family background, the team and her oncologist agreed that further analysis was warranted.
Deeper analysis with whole exome sequencing
The patient was invited for an additional round of testing using SOPHiA DDM™ Whole Exome Solution v2. An oral swab sample was collected, and the sequecing data was carefully analyzed in the SOPHiA DDM™ Platform.
Through this comprehensive approach, a pathogenic mutation associated with hereditary breast cancer was identified. Further targeted testing confirmed that the patient’s mother also carried the same mutation, establishing a hereditary link.
Impact on family management
During follow-up discussions, the team learned that the patient had a five-year-old daughter. Genetic testing revealed that the child also carried the pathogenic variant.
With early knowledge of her genetic risk, the family and healthcare providers can initiate proactive surveillance and preventive strategies from a young age — long before the typical age for routine breast cancer screening. This early intervention has the potential to significantly improve health outcomes.
This case emphasizes the importance of expanding genetic testing strategies, particularly in underserved populations where hereditary cancers may present differently, and where conventional panel-based approaches may not always be sufficient.
Note: Breast cancer in Black women often presents at younger ages and is associated with higher mortality rates1, underscoring the need for personalized genetic screening strategies.
Click through to learn more about SOPHiA DDM™ hereditary cancer and exome solutions.
References:
SOPHiA DDM™ is for Research Use Only (RUO), not for use in diagnostic procedures unless otherwise specified. Clinical interpretation and patient management decisions are the sole responsibility of qualified healthcare professionals. Patient case shared with permission and anonymized for educational purposes.
In this spotlight, Dr. Jose Claudio Casali, Head of the Department of Oncogenetics, and Dr. Dirce Maria Carraro, Head of the Clinical and Functional Genomics Group at A. C. Camargo Cancer Center share an extraordinary case that highlights the critical role of comprehensive multigene testing in hereditary cancer care. By using a custom SOPHiA DDM™ Hereditary Cancer Solution, their team was able to generate rare and clinically relevant findings that helped shape a new course of treatment and preventative care — not only for the patient, but for her entire family.
Watch the interview:
Case Overview
A 51-year-old woman was recently diagnosed with breast cancer — her second breast cancer diagnosis in 10 years.
Tumor characteristics were completely different:
Strong family history:
Variant analysis powered by the SOPHiA DDM™ Platform
A comprehensive 112-gene panel was used for genetic testing.
Three variants were identified:
Implications
Family Screening and Management
Relatives were tested:
The inheritance pattern confirmed that the variants were authentic (not technical artifacts).
Clinical Management Decisions
Based on risk assessment, the patient underwent:
Family members were enrolled in an annual whole-body MRI screening program.
Key Takeaways
Click through to learn more about SOPHiA DDM™ hereditary cancer solutions.
SOPHiA DDM™ is for Research Use Only (RUO), not for use in diagnostic procedures unless otherwise specified. Clinical interpretation and patient management decisions are the sole responsibility of qualified healthcare professionals. Patient case shared with permission and anonymized for educational purposes.
Please can you introduce yourself and share a bit about your role, institution, and the genetic services you provide?
I am a laboratory scientist working in the Molecular Diagnostics Laboratory at the National Children’s Hospital “Carlos Saenz-Herrera” in Costa Rica. Our laboratory serves as the national reference center for diagnosing genetic diseases in both children and adults. Additionally, we are part of the National Oncological Counseling Project, which has been operational since 2018. Within this project, we perform genetic analyses for adult participants across the country. I am part of the team responsible for conducting genetic tests, including whole exome sequencing and Sanger sequencing, as well as analyzing, interpreting, and reporting variants. Our laboratory collaborates closely with clinicians from various hospital specialties, holding monthly clinical meetings to discuss complex and challenging cases. This multidisciplinary approach helps improve diagnosis and patient management.
Which SOPHiA GENETICS applications do you currently use in your work?
Currently, we use the SOPHiA DDM™ Hereditary Cancer Solution v2.0, which includes 83 genes associated with hereditary cancer, and the SOPHiA DDM™ Whole Exome Solution. We rely on the SOPHiA DDM™ Platform for variant analysis.
What are the key benefits of using the SOPHiA DDM™ Platform in your lab?
Using the SOPHiA DDM™ Platform has significantly streamlined our workflow by reducing analysis time and optimizing variant interpretation. The platform provides easy access to multiple databases directly within its interface, which simplifies data contextualization.
One of the most valued features is the ability to build our own custom database. This functionality allows us to perform intra-sample comparisons (within the same run), inter-sample comparisons (across all runs over time), and inter-laboratory comparisons using SOPHiA DDM™'s tools. This is essential for validating findings and ensuring consistency in our analyses.
Having a custom database is particularly beneficial because public databases often lack adequate information about Latin American populations, especially Costa Rican populations. By maintaining our own database, we can track allele frequencies specific to our population and analyze potential founder effects or population-specific genetic behaviors. This capability not only facilitates trend analysis over time but also enhances our ability to identify patterns and anomalies in genetic data. Such insights are invaluable for developing more precise and personalized clinical strategies tailored to our population.
Your recent research using the SOPHiA DDM™ Hereditary Cancer Solution v2.0 in Costa Rica identified a prominent founder variant in the BRCA2 gene. Can you share more about this discovery and its significance?As part of our involvement in the National Oncological Counseling Project, we have analyzed approximately 1500 probands and 2300 relatives since 2018. Among these families, around 800 have hereditary breast/ovarian cancer syndrome. Notably, we observed that 43% of families diagnosed with breast/ovarian cancer have a pathogenic variant in BRCA2. Of these families with BRCA2 variants, 61% carry the c.9235delG variant.
This variant does not fall within regions typically associated with breast or ovarian cancer risk. Interestingly, it has also been identified in other types of cancer within Costa Rica, such as pancreatic and prostate cancer. These findings suggest a unique genetic architecture for breast and ovarian cancer in the Costa Rican population.
The discovery of this founder variant highlights the importance of understanding population-specific genetic markers to improve diagnostics.
How has your experience been working with the SOPHiA GENETICS team?
Our collaboration with SOPHiA GENETICS has been highly positive. The team is responsive and supportive, providing valuable guidance on how to maximize the platform’s functionalities for our specific needs.
Looking ahead, what excites you most about the future of genetic testing at National Children’s Hospital “Carlos Saenz-Herrera”?
Looking ahead, we are excited about the possibilities of integrating cutting-edge technologies into our laboratory workflows.
For instance:
- Optical Genome Mapping: This technology has enormous potential to revolutionize structural variant detection by providing high-resolution insights into chromosomal abnormalities.
- Somatic Sequencing: Expanding into somatic sequencing will enable us to analyze tumor-specific mutations more comprehensively.
These advancements will further enhance our ability to provide robust diagnostic solutions and personalized treatment strategies for patients across Costa Rica.
Elexandra Barboza-Arguedas and her team are a great example of how dedicated experts can combine technology and local knowledge to make a real difference. We’re proud to support their work as they continue to expand genetic testing in Costa Rica, uncovering insights that not only advance clinical insights today but help shape a more personalized, inclusive future for healthcare.
Click through to learn more about SOPHiA DDM™ exome and hereditary cancer solutions.
We are glad to host Dr. Davide Martorana, Senior Molecular Geneticist at the Medical Genetic Lab of the University-Hospital of Parma in Italy, who shared with us his institute’s experience with the adoption of the New Generation SOPHiA DDMTM Platform.
-Hello, Davide, thank you for joining us today for this spotlight! Could you please briefly introduce yourself and describe your role, institution, and the type of services you offer?
-Sure. My name is Davide Martorana, and I am a Senior Molecular Geneticist at the Medical Genetic Lab – a lab at the University Hospital of Parma in Italy.
As a Biologist, I am part of the clinical interpretation team for focused panels and clinical whole exome sequencing for subjects with a suggestive phenotype; after the genetic test, we provide reports with results interpretation.
-Could you please share with us which of the SOPHiA GENETICS applications and services are you currently using?
-We use two different SOPHiA GENETICS solutions, the Nephropathy Solutions (NES) and Hereditary Cancer Solutions (HCS), analysed with SOPHiA DDMTM
-What are the biggest benefits you see in the New Generation SOPHiA DDMTM Platform in terms of new features/ capabilities and user experience?
-First of all, I want to state that we are very happy and satisfied with this evolution of the SOPHiA DDMTM Platform. The feature I prefer is the personalization of the information flow about genetic variants; in fact, I am sure every analyst has a preferred workflow when evaluating a single variant; for example, I like to see immediately the population frequency, both in our single center and for all SOPHiA GENETICS customers; then, the ACMG-AMP classification with specified criteria.
In my opinion, this fact is very important, because when you must manage a lot of variants, it is important to focus fast on a few but essential info, then if you want there is the possibility to access several other additional info; in particular, I appreciate the extensive link-outs to other databases, which are very accurate and useful.
-Thank you for your kind words. Could you please share an example where the SOPHiA DDMTM Platform streamlined your laboratory workflows and supported your clinical research efforts?
-In a specific family, after genetic counseling of a twenty-week-old pregnant woman with a clinical diagnosis of Polycystic Kidney disease 1 - never investigated at a genetic level - we were asked to analyze the woman and the fetus with the Nephropathy solution kit.
After the analysis on the SOPHiA DDMTM Platform, we were able to detect the causative mutation in PKD1 gene in the mother but not in the fetus. The analyses were performed in just three days after receiving the biological samples, which was a very fast turnaround.
After that analysis, we realized the true potential of having an NGS kit coupled with software with fast, reliable, and accurate results, and this is just one simple example.
-It is great to see how our solutions are impacting your real-life clinical research and streamlining your decision-making when it matters the most. On the implementation side, how was your experience with the Setup program for SOPHiA DDMTM in terms of easiness, time spent on validation, and time to routine?
-In our experience, the Setup program for SOPHiA DDMTM was very fast and easy. In fact, after the training with SOPHiA customer support, we spent just a working for validating the entire process and personalizing the information flow before introducing it in the routine analysis. This is very important and efficient for the users.
-And how does your experience with the SOPHiA GENETICS customer support look like?
-I am extremely satisfied with SOPHiA GENETICS customer support because they are efficient and proactive, answering all our queries and addressing our issues in a very short time and with great competence and kindness. I would like to thank you on behalf of the entire team for that.
We would like to warmly thank Dr. Davide Martorana for joining us in this customer spotlight.
Are you interested in exploring how the New Generation SOPHiA DDM Platform can revolutionize your workflows? Check out our recent blog post here!
The term « SOPHIA » used by the speaker refers to SOPHiA GENETICS and its products. The opinions expressed during this presentation are these of the speaker and may not represent the opinions of SOPHiA GENETICS. SOPHiA GENETICS does not provide support in the validation of custom products for clinical use. SOPHiA DDM™ Dx Homologous Recombination Deficiency Solution is available as a CE-IVD product for In Vitro Diagnostic Use in the European Economic Area (EEA), the United Kingdom and Switzerland. SOPHiA GENETICS products are for Research Use Only and not for use in diagnostic procedures unless specified otherwise.
What is cascade testing?
Cascade testing is the practice of offering genetic testing to relatives of known carriers of pathogenic variants associated with autosomal dominant conditions. In oncology, cascade testing is performed in families affected by hereditary cancer syndromes1. The most common include hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), familial adenomatous polyposis syndrome, hereditary pancreatic cancer syndrome and gastric cancer syndrome2,3. Testing for variants associated with HBOC and LS belongs to the so-called Tier 1 testing, i.e., genomic applications, the implementation of which is supported by robust evidence4.
Cascade testing starts with first-degree relatives (parents, siblings, children) of index cases (i.e., the family member in whom a pathogenic variant was identified) and then proceeds to second- (grandparents/grandchildren, aunts/uncles, nieces/nephews, half-siblings) and third-degree relatives (great-grandparents/great-grandchildren, first cousins)1.
Most hereditary cancer syndromes follow the autosomal dominant inheritance pattern. Therefore, the first-, second- and third-degree relatives have, respectively, a 50%, 25%, and 12.5% probability of inheriting the predisposition to develop cancer (see Figure 1)1. For some pathogenic variants of genes associated with hereditary cancer syndromes, such as BRCA1/2, the penetrance is high5. Establishing accurate estimates of penetrance and relative risk for genes implicated in hereditary cancer syndromes is an ongoing task3.
Figure 1. Heritable pathogenic variants increase the risk of developing cancer at a younger age (left). Cascade genetic testing is the practice of testing the relatives of known carriers (right)1.
Why is cascade testing important?
At the level of an individual and their family, cascade testing has two important goals. The first goal is to identify relatives that carry the familial pathogenic variant and require personalized cancer risk management1. The second goal is to exclude the non-carriers from intensive cancer surveillance and prevention interventions1. The detection of pathogenic variants in individuals at a reproductive age may lead to decisions of assisted reproduction or prenatal diagnosis. In the case of actionable monogenic conditions, cascade testing may reduce adverse health outcomes in cohorts of relatives1.
At the societal level, cascade testing has important clinical and research implications for oncology. It can further our knowledge of hereditary cancers and is a cost-effective way of identifying unaffected individuals at-risk, thus, providing important information to plan long-term resources necessary to cope with hereditary cancers. Moreover, today’s testing is needed to tailor future approaches in cascade testing1.
Figure 2. Cascade testing involves genetic counseling before and after the test, risk estimation and management, and has treatment implication7.
What are the barriers to cascade testing?
Despite the advantages of cascade testing, its uptake is low. The reported rates of uptake of cascade testing in HBOC and LS equals ~50% and the underutilization of testing results in missed opportunities of cancer prevention1. In a recent Swiss study, there was a 25-50% response rate to invitations to cascade testing and at least one-in-three individuals at risk did not undergo testing. An index case possesses an average of 10 relatives eligible for testing, while the average rate of genetic tests per index case is only 1.51.
There are several barriers to cascade testing6,7. These include ineffective family communication of genetic risk information, low knowledge of cascade testing among index cases and primary care providers, and geographic barriers to receiving genetic services. Cascade testing uptake is also lower among male than female relatives and in distant compared to first-degree relatives. A facilitator of adherence to cascade testing is the parents’ desire to understand their children’s risk6. “Dear family” letters, digital chatbots (a technology-based simulated conversations), and direct contact programs have been shown to be effective in motivating cascade testing8.
Several initiatives exist to promote cascade testing. One such enterprise is the Cascade Resources Network, an independently run, non-profit organization that offers access to genetic testing, genetic counseling, variant interpretation, screening guidelines, and forums and support. It was developed by Memorial Sloan Kettering Cancer Center (MSK) fellows, Ryan Kahn and Sushmita Gordhandas. The network was created to increase the rate of genetic testing among relatives of patients with inherited cancer risk variants to help identify cancer early in families and, ultimately, to prevent future cancers. Similarly, the Swiss Cancer Genetic Predisposition Cascade Screening Consortium was established in 2016 to foster research related to the hereditary cancer predisposition. In particular, the Consortium promotes the CASCADE cohort, a family-based open-ended cohort targeting HBOC and LS variant-harboring families to elicit factors that enhance adherence to testing (NCT03124212).
Analyze genetic predisposition to cancer with the SOPHiA DDM™ Platform
Multi-gene testing is an efficient, affordable, and guideline-recommended9 approach to cascade testing as it allows for comprehensive assessment of biologically relevant hereditary cancer genes. The SOPHiA DDM™ Platform supports various next generation sequencing (NGS)-based Hereditary Cancer Applications to help clinician researchers characterize the complex mutational landscape associated with hereditary cancer disorders.
Powered by advanced analytics, users can detect challenging variants in a streamlined sample-to-report workflow, including:
Variant pathogenicity levels are assigned using machine learning complemented by guideline-driven ranking, helping to prioritize relevant variants and reduce interpretation time. Furthermore, deeper variant exploration is supported by Alamut™ Visual Plus, a full-genome browser that integrates numerous curated genomic and literature databases, guidelines, missense and splicing predictors.
To learn more about SOPHiA DDM™ for Hereditary Cancers, explore here or request a demo here.
References
1. Sarki M, et al. Cancers (Basel) 2022;14:1636.
2. Brown GR, et al. JAAPA 2020;33(12):10-16.
3. Mighton C, Lerner-Ellis JP. Genes Chromosomes Cancer 2022;61(6):356-381.
4. Dotson WD, et al. Clin Pharmacol Ther 2014;95(4):394-402.
5. Chen S, Parmigiani G. J Clin Oncol 2007;25(11):1329-1333.
6. Roberts MC, et al. Health Aff (Millwood) 2018;37(5):801-808.
7. O'Neill SC, et al. Hered Cancer Clin Pract 2021;19(1):40.
8. Campbell-Salome G, et al. (2022) Transl Behav Med 2022;12(7):800–809.
9. Daly MB, et al. J Natl Compr Canc Netw. 2021 Jan 6;19(1):77-102.
The HGVS nomenclature guidelines are used worldwide for genetic variant interpretation but can seem complicated and difficult to understand and apply. That is why we have created this beginner’s guide to mutation nomenclature using the HGVS recommendations, with clear visual examples that break down the process into bitesize pieces.
1. What is HGVS nomenclature?
2. How to read mutation nomenclature: Breaking down the variant description
2.1 Reference sequence e.g., NM
2.2 Description of variant e.g., c.4375C>T
2.3 Predicted consequence e.g., p.(Arg1459*)
3. The 3 prime rule for mutation
4. Final thoughts and helpful tool
The Human Genome Variation Society (HGVS) nomenclature standard was developed to prevent the misinterpretation of variants in DNA, RNA, and protein sequences. The HGVS nomenclature standard is used worldwide, especially in clinical diagnostics, and is authorized by the Human Genome Organisation (HUGO).1,2
HGVS General Terminology Recommendations1
| X Do not use | ✔️ Recommended terminology |
| Mutation or polymorphism | Variant, change, allelic variant Can be used for cancer tissue: Mutation load and tumor mutation burden |
| Pathogenic | Affects function, disease-associated, phenotype-associated |
HGVS follow recognized standards for the nomenclature of DNA and RNA nucleotides, the genetic code, amino acid descriptions, and cytogenetic band position in chromosomes.3
The HGVS recommendations for mutation nomenclature state that the format of a complete variant description should first include the reference sequence, followed by the variant description, and then the predicted consequence in parentheses. For example, NM-004006.2:c.4375C>T p.(Arg1459*) (Figure 1).
The HGVS nomenclature recommendations for sequence variants state that a complete variant description should begin with the reference sequence.1 The reference sequence accession number begins with a two-letter abbreviation (explained in Table 1), followed by a multi-digit number, and finally a version number.
Table 1. Meaning of the two-letter abbreviation at the beginning of a reference sequence accession number.
| Abbreviation | Reference sequence based on a: |
| NC | Chromosome |
| NG | Gene or genomic region |
| LRG | Locus Reference Genomic sequence: Gene or genomic region, used in a diagnostic setting |
| NM | Protein-coding RNA (mRNA) |
| NR | Non-protein-coding RNA |
| NP | Protein (amino acid) sequence |
The variant description begins by depicting the type of reference sequence used (c = coding DNA sequence, g = genomic reference sequence). When a protein-coding reference sequence is used (c), the nucleotide numbering begins with a 1, which represents the first position in the protein-coding region (the A of the translation-initiating ATG), and ends at the last position of the stop codon. Thus, if you divide the position number by 3, you can identify the affected amino acid in the protein sequence e.g., using the same example as above, 4375/3 = 1459, indicating that the predicted consequence affects amino acid 1459, which is an arginine. Different variants are indicated using different notations (explained in Table 2).
Table 2. HGVS notation and examples for the most common types of mutations2
| Notation | Example | Explanation |
| > | c.4375C>T | Substitution of the C nucleotide at position c.4375 with a T |
| del | c.4375_4379del or c.4375_4379delCGATT | Nucleotides from position c.4375 to c.4379 deleted |
| dup | c.4375_4385dup or c.4375_4385dupCGATTATTCCA | Nucleotides from position c.4375 to c.4385 duplicated |
| ins | c.4375_4376insACCT | ACCT inserted between positions c.4375 and c.4376 |
| delins | c.4375_4376delinsACTT or c.4375_4376delCGinsAGTT | Nucleotides from position c.4375 to c.4376 (CG) are deleted and replaced by ACTT |
When only DNA has been analyzed, the RNA- and protein-level consequences of the variant can only be predicted, and should thus be reported in parentheses e.g., p.(Arg1459*) is the predicted effect at protein level (p) for the example described above.
For all variant descriptions using HGVS nomenclature, the nucleotide at the most 3’ position of the variation in the reference sequence is arbitrarily assigned to have changed (see how to apply this rule in Figure 2).4 The exception is for deletions/duplications around exon junctions for which shifting the variant 3’ would place it in the next exon.5
Although the HGVS recommendations can be difficult to understand and might take a bit of getting used to, if you break them down and refer to the examples in this guide, you are on the road to success!
If you want to accelerate your variant annotation and interpretation, Alamut™ Visual Plus is a comprehensive, full genome browser for efficient and user-friendly variant interpretation. The software accelerates the complex and time-consuming assessment of variants thanks to its user-friendly interface and integrated features for variant annotation and analysis.
Find out how Alamut™ Visual Plus applies the HGVS nomenclature recommendations to ensure that variant annotation follows the universally applied standards for variant analysis, interpretation, and reporting in our dedicated Technical Note.
Alamut™️ Visual Plus is for Research Use Only. Not for use in diagnostic procedures.
References
SOPHiA GENETICS products are for Research Use Only and not for use in diagnostic procedures unless specified otherwise.
SOPHiA DDM™ Dx Hereditary Cancer Solution, SOPHiA DDM™ Dx RNAtarget Oncology Solution and SOPHiA DDM™ Dx Homologous Recombination Deficiency Solution are available as CE-IVD products for In Vitro Diagnostic Use in the European Economic Area (EEA), the United Kingdom and Switzerland. SOPHiA DDM™ Dx Myeloid Solution and SOPHiA DDM™ Dx Solid Tumor Solution are available as CE-IVD products for In Vitro Diagnostic Use in the EEA, the United Kingdom, Switzerland, and Israel. Information about products that may or may not be available in different countries and if applicable, may or may not have received approval or market clearance by a governmental regulatory body for different indications for use. Please contact us to obtain the appropriate product information for your country of residence.
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