Submissions for variant NM_007294.4(BRCA1):c.4006A>T (p.Ser1336Cys)

gnomAD frequency: 0.00001  dbSNP: rs976725810

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579559	SCV000683143	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1336 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006285). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.0331 and 0.316 based on co-occurrence with a pathogenic covariant and family history of 1.0331 and 0.316, respectively (PMID: 31131967). This variant has been identified in 1/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000805852	SCV000945825	likely benign	Hereditary breast ovarian cancer syndrome	2023-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579559	SCV001183288	likely benign	Hereditary cancer-predisposing syndrome	2023-05-09	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	RCV001564750	SCV001787959	likely benign	not provided	2019-08-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000579559	SCV003852451	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).