Submissions for variant NM_007294.4(BRCA1):c.378A>G (p.Gln126=)

gnomAD frequency: 0.00001  dbSNP: rs786201256

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495284	SCV000578104	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/).
Ambry Genetics	RCV000163181	SCV000213702	likely benign	Hereditary cancer-predisposing syndrome	2016-11-03	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.
Color Diagnostics, LLC DBA Color Health	RCV000163181	SCV000688452	likely benign	Hereditary cancer-predisposing syndrome	2017-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501018	SCV000699072	likely benign	not specified	2019-08-21	criteria provided, single submitter	clinical testing
Invitae	RCV000637353	SCV000758808	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590434	SCV000888898	likely benign	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590434	SCV000591260	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Gln126Gln was identified in the ClinVar database, submitted by Ambry Genetics with a classification of “likely benign”. The variant was not identified in the literature, nor was it identified in other database searches (dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, GeneInsight COGR, BIC, UMD). The variant does not result in a change of amino acid and is not located in a known consensus splice site; however, four of five in silico splicing prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a cryptic 3’ splice site in the region. It should be noted that these predictions are not enough to assume pathogenicity as no functional data to support these predictions was identified. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.