Submissions for variant NM_007294.4(BRCA1):c.3556C>T (p.Leu1186Phe)

dbSNP: rs1555587505

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000637424	SCV000758881	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-14	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 531251). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1186 of the BRCA1 protein (p.Leu1186Phe).
Color Diagnostics, LLC DBA Color Health	RCV001186451	SCV001352855	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1186 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 not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282275	SCV002570843	uncertain significance	not specified	2022-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001186451	SCV002616561	likely benign	Hereditary cancer-predisposing syndrome	2020-10-23	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001186451	SCV003850182	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).
PreventionGenetics, part of Exact Sciences	RCV003424212	SCV004109756	uncertain significance	BRCA1-related condition	2023-05-10	criteria provided, single submitter	clinical testing	The BRCA1 c.3556C>T variant is predicted to result in the amino acid substitution p.Leu1186Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/531251/). Of note, this variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV003441987	SCV004167883	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3675C>T; This variant is associated with the following publications: (PMID: 31911673)