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
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
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
Color RCV000130861 SCV000684025 likely benign Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120368 SCV000592258 uncertain significance not specified 2014-01-16 criteria provided, single submitter 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
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.
ITMI RCV000120368 SCV000084520 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120368 SCV000695213 uncertain significance not specified 2017-12-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9104A>C (p.Tyr3035Ser) variant involves the alteration of a conserved nucleotide and the affected residue (Tyr3035) is located in nucleic acid-binding region/OB-fold domain. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 24/371794 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000646, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous patients with breast and/or ovarian cancer, however without strong evidence for pathogenicity. In three individuals reported in UMD database, this variant co-occurred with another truncating variant, BRCA1 c.2603C>G (p.Ser868X), BRCA2 c.1540_1549del (p.Glu514MetfsX8), and BRCA2 c.7913_7917delTTCCT (p.Phe2638X), strongly supporting for the benign outcome. In addition, this variant was also found to co-occur with BRCA2 S1882X in patient in literature (Shimelis_2017). The same publication found that this variant confers a moderate risk to breast cancer in Caucasian population (odds ratio: 2.5; 95% CI 1.05 to 6.05; p-value: 0.038). In functional studies, the variant collectively displayed partially deficient BRCA2 activity (Shimelis_2017). The variant rescued 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. Clinical diagnostic laboratories/databases have provided conflicting interpretations of pathogenicity: benign (1), likely benign (2) and uncertain significance (4). Based on the overall data, it is possibly a moderate risk variant although this is not a high penetrance causative variant. Other case-control studies may require to confirm this. Therefore, this variant is currently classified as variant of uncertain significance-possibly benign.
Invitae RCV000045717 SCV000073730 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-17 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

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