Submissions for variant NM_007294.4(BRCA1):c.3248T>C (p.Met1083Thr)

dbSNP: rs786203958

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167486	SCV000218344	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	clinical testing	The p.M1083T variant (also known as c.3248T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 3248. The methionine at codon 1083 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505886	SCV000600322	uncertain significance	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167486	SCV000688427	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1083 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. A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.0331 and 1.6021 based on co-occurrence and family history, respectively (PMID: 31131967). 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.
Invitae	RCV001202434	SCV001373546	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1083 of the BRCA1 protein (p.Met1083Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 187732). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167486	SCV003848997	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).