Submissions for variant NM_000059.4(BRCA2):c.3553A>G (p.Thr1185Ala)

dbSNP: rs786202485

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165322	SCV000216044	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.T1185A variant (also known as c.3553A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3553. The threonine at codon 1185 is replaced by alanine, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686649	SCV000814177	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1185 of the BRCA2 protein (p.Thr1185Ala). This variant is not present in population databases (gnomAD no frequency). 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. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185827). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165322	SCV003846698	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	RCV004535110	SCV004103915	uncertain significance	BRCA2-related disorder	2023-09-29	criteria provided, single submitter	clinical testing	The BRCA2 c.3553A>G variant is predicted to result in the amino acid substitution p.Thr1185Ala. 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. In the ClinVar database, this variant has been interpreted as 'uncertain' or 'likely benign' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/185827/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003995411	SCV004845180	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1185 of the BRCA2 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 hereditary cancer 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.