Submissions for variant NM_007294.4(BRCA1):c.5304C>T (p.Cys1768=)

gnomAD frequency: 0.00012  dbSNP: rs138493864

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495218	SCV000578387	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000159892	SCV000209989	benign	not specified	2014-04-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163518	SCV000214076	likely benign	Hereditary cancer-predisposing syndrome	2014-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001086394	SCV000253514	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163518	SCV000683285	likely benign	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159892	SCV000699235	benign	not specified	2019-03-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5304C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 277382 control chromosomes, predominantly at a frequency of 0.00042 within the African subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (3.6e-05 vs 0.001). This variant has been reported in the literature in one individual affected with Breast and Ovarian Cancer (Suter_2004). This variant has also been reported in 3/9884 women who are older than age 70 and cancer free, suggesting this variant does not associate with cancer. One publication reports experimental evidence evaluating an impact on protein function and showed this variant had normal function (Findlay_2018). Four 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000495218	SCV000786180	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-03-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590732	SCV000887718	benign	not provided	2021-02-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590732	SCV001474395	likely benign	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163518	SCV002537838	likely benign	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003952797	SCV004785076	likely benign	BRCA1-related condition	2019-09-06	criteria provided, single submitter	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).
Brotman Baty Institute, University of Washington	RCV000495218	SCV001238100	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro