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

gnomAD frequency: 0.00002  dbSNP: rs55730620

Total submissions: 11

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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231524	SCV000283277	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-23	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).
All of Us Research Program, National Institutes of Health	RCV000076945	SCV004846670	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing
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