Submissions for variant NM_000059.4(BRCA2):c.3749A>G (p.Glu1250Gly)

gnomAD frequency: 0.00004  dbSNP: rs56400215

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044256	SCV000072269	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129769	SCV000184578	likely benign	Hereditary cancer-predisposing syndrome	2024-10-03	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	RCV000212231	SCV000210323	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 21120943, 30254663, 22476429, 33471991); Also known as 3977A>G; This variant is associated with the following publications: (PMID: 21120943, 22476429, 25556971, 30254663, 31131967, 33471991, 29884841, 32377563)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212231	SCV000887796	uncertain significance	not provided	2019-12-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129769	SCV000903264	likely benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194411	SCV001363946	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3749A>G (p.Glu1250Gly) 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 246920 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3749A>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (e.g. Caux-Moncoutier_2011, Lu_2012, Zuntini_2018, Dorling_2021). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 21120943, 22476429, 30254663, 33471991). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, and three as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129769	SCV003846839	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	RCV000113214	SCV004845216	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113214	SCV000146291	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113214	SCV004228396	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)