Submissions for variant NM_007294.4(BRCA1):c.3636A>G (p.Ser1212=)

gnomAD frequency: 0.00002  dbSNP: rs148038877

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494812	SCV000578220	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	RCV000123913	SCV000167295	benign	not specified	2014-02-24	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	RCV000163075	SCV000213574	likely benign	Hereditary cancer-predisposing syndrome	2014-10-08	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	RCV001086581	SCV000253501	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163075	SCV000688443	likely benign	Hereditary cancer-predisposing syndrome	2016-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123913	SCV000699048	likely benign	not specified	2019-02-22	criteria provided, single submitter	clinical testing	Variant summary: The variant, BRCA1 c.3636A>G 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 8.1e-06 in 246060 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3636A>G has been reported in the literature in individuals affected with breast and ovarian cancer (Judkins_2005, Anczukow_2008). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In our internal database, co-occurrence with another pathogenic variant has been reported (CHEK2 c.1368dupA, p.Glu457fsX33) for this variant, providing supporting evidence for a benign role. A functional study using minigene assay reports that it was one of the variants that did not dramatically alter splicing through disruption of an ESE (Anczukow_2008). The exact extent of functional impairment was not provided in the study. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001354426	SCV002046917	benign	not provided	2023-05-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001354426	SCV002049558	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354426	SCV001549040	uncertain significance	not provided		no assertion criteria provided	clinical testing