Submissions for variant NM_000059.4(BRCA2):c.10247A>C (p.Lys3416Thr)

gnomAD frequency: 0.00001  dbSNP: rs369663895

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215106	SCV000277706	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing	The p.K3416T variant (also known as c.10247A>C), located in coding exon 26 of the BRCA2 gene, results from an A to C substitution at nucleotide position 10247. The lysine at codon 3416 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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	RCV000215106	SCV001343444	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 3416 of the BRCA2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250344 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349646	SCV001544001	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 3416 of the BRCA2 protein (p.Lys3416Thr). This variant is present in population databases (rs369663895, gnomAD 0.0009%). 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: 233352). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998483	SCV005624316	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing	The BRCA2 c.10247A>C (p.Lys3416Thr) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/250344 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.