Submissions for variant NM_000059.4(BRCA2):c.3715A>G (p.Lys1239Glu)

gnomAD frequency: 0.00006  dbSNP: rs374191973

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704061	SCV000210321	likely benign	not provided	2021-06-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537690	SCV000635301	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575098	SCV000665037	likely benign	Hereditary cancer-predisposing syndrome	2019-09-16	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.
Color Diagnostics, LLC DBA Color Health	RCV000575098	SCV000683576	likely benign	Hereditary cancer-predisposing syndrome	2017-03-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000144184	SCV001139070	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160068	SCV001338198	likely benign	not specified	2020-02-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3715A>G (p.Lys1239Glu) 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 8e-06 in 249020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3715A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=1). Based on the evidence outlined above, and in consideration of the prevailing consensus, the variant was classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160068	SCV002761154	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575098	SCV003846817	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	RCV000144184	SCV004845207	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-28	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000144184	SCV000189257	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532626	SCV004713688	likely benign	BRCA2-related disorder	2024-01-19	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).