Submissions for variant NM_000059.4(BRCA2):c.6553G>A (p.Ala2185Thr)

dbSNP: rs746070652

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165385	SCV000216112	uncertain significance	Hereditary cancer-predisposing syndrome	2014-08-21	criteria provided, single submitter	clinical testing	The p.A2185T variant (also known as c.6553G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6553. The alanine at codon 2185 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with 6501 coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 64000 alleles tested) in our clinical cohort. 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 p.A2185T remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637749	SCV000759224	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-19	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 185884). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2185 of the BRCA2 protein (p.Ala2185Thr).
GeneDx	RCV001580461	SCV001817855	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 6781G>A
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165385	SCV003847264	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).