ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9583A>G (p.Thr3195Ala)

gnomAD frequency: 0.00001  dbSNP: rs80359227
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000045861 SCV000073874 likely benign Hereditary breast ovarian cancer syndrome 2024-01-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129471 SCV000184241 likely benign Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000083162 SCV000296504 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000083162 SCV000487986 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2015-12-10 criteria provided, single submitter clinical testing
GeneDx RCV001705703 SCV000532127 likely benign not provided 2019-05-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16905680, 25348012, 26295337, 23704879, 30212499, 28726806)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000427171 SCV000695253 uncertain significance not specified 2024-08-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9583A>G (p.Thr3195Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9583A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Simard_2007, Dutil_2019, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent study examining variants of uncertain significance in BRCA1/2, the French national COVAR (cosegregation variant) study, classified the variant as likely benign/benign based on variant cosegregation analyses and segregation data, however the detailed data was not available for review (Caputo_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16905680, 23704879, 28726806, 34597585, 31780696, 32438681). ClinVar contains an entry for this variant (Variation ID: 52872). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000129471 SCV000911111 benign Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000427171 SCV001158035 uncertain significance not specified 2018-11-29 criteria provided, single submitter clinical testing The BRCA2 c.9583A>G; p.Thr3195Ala variant (rs80359227), is reported in the literature in at least one individual with a family history of breast and/or ovarian cancer (Simard 2007). This variant is reported as uncertain significance/likely benign by multiple laboratories in ClinVar (Variation ID: 52872), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 3195 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr3195Ala variant is uncertain at this time. References: Simard J et al. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. J Med Genet. 2007 Feb;44(2):107-21.
All of Us Research Program, National Institutes of Health RCV000083162 SCV004846192 benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-04-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083162 SCV000115236 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083162 SCV000147669 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing

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