ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5921C>T (p.Thr1974Ile)

gnomAD frequency: 0.00002  dbSNP: rs55730620
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166046 SCV000216807 likely benign Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Invitae RCV000231524 SCV000283277 likely benign Hereditary breast ovarian cancer syndrome 2023-10-16 criteria provided, single submitter clinical testing
GeneDx RCV001697138 SCV000534773 uncertain significance not provided 2023-08-01 criteria provided, single submitter clinical testing Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Tsaousis et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6149C>T; This variant is associated with the following publications: (PMID: 29884841, 32377563, 31159747, 31911673)
Counsyl RCV000076945 SCV000784847 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2017-01-04 criteria provided, single submitter clinical testing
GeneKor MSA RCV000166046 SCV000821941 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000436824 SCV001623382 uncertain significance not specified 2023-11-08 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5921C>T (p.Thr1974Ile) 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 4e-06 in 250828 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5921C>T has been reported in the literature as a VUS in at-least one individual undergoing a multigene panel for hereditary cancer (example, Tsaousis_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31159747). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance until additional unequivocal evidence supporting a non-actionable outcome are reported/identified.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001697138 SCV002047288 uncertain significance not provided 2021-04-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000166046 SCV002053562 likely benign Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000166046 SCV003850782 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP) RCV000076945 SCV000108742 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2009-12-07 no assertion criteria provided clinical testing

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