Submissions for variant NM_000059.4(BRCA2):c.4718G>A (p.Cys1573Tyr)

gnomAD frequency: 0.00001  dbSNP: rs56249050

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081098	SCV000072489	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132250	SCV000187333	likely benign	Hereditary cancer-predisposing syndrome	2018-11-14	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	RCV000758898	SCV000518764	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20609467, 10699917)
Color Diagnostics, LLC DBA Color Health	RCV000132250	SCV000683648	likely benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000077337	SCV000786380	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758898	SCV000887823	likely benign	not provided	2019-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000445221	SCV000918863	likely benign	not specified	2021-09-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4718G>A (p.Cys1573Tyr) 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 8e-06 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4718G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Spitzer_2000, Tutt_2010, He_2016, Gaia-Oltean_2021). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.1687C>T, p.Q563X, Tutt_2010; BRCA2 c.4456_4459delGTTA, p.Val1486AsnfsX5, internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132250	SCV003852044	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)	RCV000077337	SCV000109134	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077337	SCV000146474	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing