Submissions for variant NM_000059.4(BRCA2):c.5170A>G (p.Ile1724Val)

gnomAD frequency: 0.00023  dbSNP: rs35335654

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131376	SCV000186352	likely benign	Hereditary cancer-predisposing syndrome	2019-03-20	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	RCV000587993	SCV000210611	likely benign	not provided	2020-10-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25348012)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206856	SCV000260001	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160227	SCV000694834	benign	not specified	2021-09-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5170A>G (p.Ile1724Val) 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 4.5e-05 in 242492 control chromosomes, predominantly at a frequency of 0.00071 within the African or African-American subpopulation in the gnomAD database. In addition, this variant was found in 5/2559 African individuals over age 70 with no history of cancer. To our knowledge, no occurrence of c.5170A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.211A>G , p.Arg71Gly; BRCA1 c.470_471delCT , p.Ser157X; BRCA1 943ins10), providing supporting evidence for a benign role. Six 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587993	SCV000887843	likely benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131376	SCV000903441	benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160227	SCV002065240	likely benign	not specified	2021-04-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000131376	SCV004814098	likely benign	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000082938	SCV000115012	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000082938	SCV000146556	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677857	SCV000804018	likely benign	Ovarian cancer	2018-01-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529872	SCV004753149	likely benign	BRCA2-related disorder	2022-03-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).