Submissions for variant NM_007294.4(BRCA1):c.457A>C (p.Ser153Arg)

gnomAD frequency: 0.00003  dbSNP: rs28897674

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001085851	SCV000076611	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131372	SCV000186348	likely benign	Hereditary cancer-predisposing syndrome	2019-03-21	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.
GeneDx	RCV000588983	SCV000209913	likely benign	not provided	2019-07-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23161852, 15385441, 16267036, 17719744)
Counsyl	RCV000031181	SCV000489049	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131372	SCV000683194	likely benign	Hereditary cancer-predisposing syndrome	2017-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234929	SCV000699157	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.457A>C (p.Ser153Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.457A>C has been reported in the literature in at least one individual undergoing genetic testing (Judkins_2005). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant have been reported (BRCA2 c.9253_9254insA, p.Thr3085Asnfs) in BIC database, providing supporting evidence for a benign role. One functional study in the literature suggests that the variant does not significantly affect BRCA1 function as demonstrated by two different DNA repair assays(Towler_2013). The following publications have been ascertained in the context of this evaluation (PMID: 29416040, 16267036, 17719744, 23161852, 30617304, 34981296). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=5) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588983	SCV001133588	likely benign	not provided	2023-06-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031181	SCV000053781	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2013-01-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031181	SCV000145588	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031181	SCV004244167	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing