Submissions for variant NM_000059.4(BRCA2):c.3503T>C (p.Met1168Thr)

dbSNP: rs80358598

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526728	SCV000635284	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-18	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 1168 of the BRCA2 protein (p.Met1168Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with the family history of breast cancer (PMID: 16826315, 25556971). This variant is also known as 3731T>C. ClinVar contains an entry for this variant (Variation ID: 462294). 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 BRCA2 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.
Ambry Genetics	RCV000571371	SCV000668846	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	The p.M1168T variant (also known as c.3503T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3503. The methionine at codon 1168 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Peixoto A et al. Fam. Cancer. 2006 Jul;5:379-87; Trujillano D et al. J Mol Diagn. 2015 Mar;17:162-70; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571371	SCV000903890	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1168 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family with a history of breast and/or ovarian cancer (PMID: 16826315). This variant has been identified in 1/250868 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002476133	SCV002774484	uncertain significance	not provided	2021-06-09	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571371	SCV003846657	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).
MGZ Medical Genetics Center	RCV003607299	SCV004543889	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BP5_SUP
All of Us Research Program, National Institutes of Health	RCV003999055	SCV004845174	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1168 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family with a history of breast and/or ovarian cancer (PMID: 16826315). This variant has been identified in 1/250868 chromosomes 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.