ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9104A>C (p.Tyr3035Ser) (rs80359165)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000589726 SCV000073730 likely benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130861 SCV000185760 likely benign Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000589726 SCV000210679 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9104A>C at the cDNA level, p.Tyr3035Ser (Y3035S) at the protein level, and results in the change of a Tyrosine to a Serine (TAT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 9332A>C. BRCA2 Tyr3035Ser has been reported in individuals with breast, ovarian, and prostate cancer, as well as in healthy controls (Borg 2010, Kote-Jarai 2011, Alsop 2012, Bodian 2014, Dodova 2015, Muendlein 2015, Kraus 2017, Shimelis 2017). Shimelis et al. (2017) suggest that this is a hypomorphic variant based on functional studies demonstrating this variant?s ability to rescue BRCA2-deficient mouse embryonic stem cell lethality, reduced homology-directed repair activity, decreased ability to bind single-stranded DNA, and partial sensitivity to PARP inhibitors. BRCA2 Tyr3035Ser was observed at an allele frequency of 0.01% (15/125,228) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Tyr3035Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120368 SCV000592258 uncertain significance not specified 2014-01-16 criteria provided, single submitter clinical testing
Color RCV000130861 SCV000684025 likely benign Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120368 SCV000695213 uncertain significance not specified 2019-01-11 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA2 c.9104A>C (p.Tyr3035Ser) results in a non-conservative amino acid change located in the DNA-binding domain (Shimelis 2017, Guidugli 2018) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 371794 control chromosomes (gnomAD, and publication data: Dodova 2015, Shimelis_2017), and was predominantly observed within the Non-Finnish European subpopulation at a frequency of 0.00012 in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00012 vs 0.00075), allowing no conclusion about variant significance. The variant, c.9104A>C, has been reported in the literature in several individuals affected with prostate cancer, breast cancer and ovarian cancer (Kote-Jari 2011, Moghadasi 2013, Alsop 2012, Muendlein 2015, Dodova 2015, Shimelis 2017, Sadowski 2017, Alvarez 2017, Jakimovska 2018, Zuntini 2018), however also was found in several healthy controls (Dodova 2015, Shimelis 2017). These reports, however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2603C>G (p.Ser868X), BRCA2 c.1540_1549del (p.Glu514MetfsX8) and BRCA2 c.7913_7917delTTCCT (p.Phe2638X) in the UMD database; and BRCA2 c.5645C>A (p.Ser1882X) in the literature (Shimelis 2017)), providing supporting evidence for a benign role. Multiple independent functional studies reporting this variant have collectively demonstrated a partially deficient BRCA2 activity, revealing decreased DNA binding (Shimelis 2017), with somewhat decreased homology-directed DNA repair (HDR) capacity, what was considered close to neutral in several assays (Shimelis 2017, Guidugli 2018, Mesman 2018), mostly retained ability to rescue lethality in complementation assays (Shimelis 2017, Mesman 2018) as well as partial sensitivity to PARP inhibitors (Shimelis 2017) or cisplatin (Mesman 2018). One case-control study found that this variant was associated with moderately increased risks of breast cancer for Caucasian women (OR=2.52; P=0.04), and while the number of cases and controls with the Y3035S variant were relatively small, this moderate risk estimate was supported by family pedigree analysis, showing partial co-segregation with breast cancer (Shimelis 2017). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant with conflicting assessments (three calling it likely benign, and three classifying it as a VUS). Based on the evidence outlined above, though the variant of interest might be a hypomorphic variant associated with a moderate risk for breast cancer, it is not a high penetrance causative variant. Further case-control studies may be necessary to confirm the above conclusions, therefore the variant was classified as uncertain significance-possibly benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031794 SCV000744554 uncertain significance Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031794 SCV000054402 benign Breast-ovarian cancer, familial 2 2011-08-18 no assertion criteria provided clinical testing
ITMI RCV000120368 SCV000084520 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031794 SCV000147538 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000045717 SCV000586990 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-14 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031794 SCV000733330 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735620 SCV000863758 uncertain significance Breast and/or ovarian cancer 2013-10-11 no assertion criteria provided clinical testing

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