Submissions for variant NM_000059.4(BRCA2):c.5737T>G (p.Cys1913Gly)

dbSNP: rs80358799

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130867	SCV000185767	likely benign	Hereditary cancer-predisposing syndrome	2018-08-01	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	RCV000588195	SCV000279232	uncertain significance	not provided	2024-02-01	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 individual(s) with personal and/or family history of ovarian cancer (PMID: 36169650); Also known as 5965T>G; This variant is associated with the following publications: (PMID: 29884841, 23231788, 16683254, 30287823, 30212499, 32377563, 31176623, 36169650, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257905	SCV000549884	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588195	SCV000600661	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in unaffected control individuals (PMID: 30287823 (2018)). In a large scale breast cancer association study, this variant was observed in individuals with breast cancer as well as unaffected study controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168581	SCV000694897	uncertain significance	not specified	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5737T>G (p.Cys1913Gly) results in a non-conservative amino acid change located in the BRCA2 repeat region (IPR002093) of 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 3.6e-06 in 275934 control chromosomes (gnomAD and Momozawa 2018). 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.5737T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000082948	SCV000785891	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130867	SCV000903518	likely benign	Hereditary cancer-predisposing syndrome	2017-10-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149769	SCV003838164	uncertain significance	Breast and/or ovarian cancer	2022-02-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130867	SCV003849065	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).
Sharing Clinical Reports Project (SCRP)	RCV000082948	SCV000115022	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-12-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000082948	SCV000146684	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing