Submissions for variant NM_000059.4(BRCA2):c.4372C>T (p.His1458Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80358672

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044399	SCV000072412	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216745	SCV000273069	likely benign	Hereditary cancer-predisposing syndrome	2021-09-21	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.
GeneDx	RCV000480609	SCV000570720	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (Anwar et al., 2016; Guo et al., 2020; Kim et al., 2020; Zhang et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4600C>T; This variant is associated with the following publications: (PMID: 31131967, 31837001, 27221885, 10923033, 31825140, 28062276, 32377563, 31853058, 27157322, 29884841, 35918668, 31907386)
Color Diagnostics, LLC DBA Color Health	RCV000216745	SCV000683613	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1458 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and an individual affected with prostate cancer (PMID: 27221885, 31214711). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001673). This variant has been identified in 7/275926 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175060	SCV001338607	uncertain significance	not specified	2021-05-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4372C>T (p.His1458Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 244556 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4372C>T has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (e.g. Anwar_2016, Guo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA1 c.181T>G, p.Cys61Gly), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480609	SCV002046332	uncertain significance	not provided	2020-10-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216745	SCV003850456	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	RCV000077323	SCV004845674	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1458 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and an individual affected with prostate cancer (PMID: 27221885, 31214711). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001673). This variant has been identified in 7/275926 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077323	SCV000109120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-03-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077323	SCV000146414	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250512	SCV002520789	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only