Submissions for variant NM_000059.4(BRCA2):c.6941C>A (p.Thr2314Lys)

dbSNP: rs1177474377

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587992	SCV000695003	uncertain significance	not provided	2016-03-21	criteria provided, single submitter	clinical testing	Variant summary: c.6941C>A affects a non-conserved nucleotide, resulting in amino acid change from Thr to Lys. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 1/115324 control chromosomes at a frequency of 0.0000087, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007503). The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories nor was evaluated for functional impact by in vivo/vitro studies. Due to the absence of clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690922	SCV000818653	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 2314 of the BRCA2 protein (p.Thr2314Lys). This variant is present in population databases (no rsID available, 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: 495492). 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	RCV002367987	SCV002661878	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-14	criteria provided, single submitter	clinical testing	The p.T2314K variant (also known as c.6941C>A), located in coding exon 12 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6941. The threonine at codon 2314 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587992	SCV002757373	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 7169C>A
GenomeConnect - Invitae Patient Insights Network	RCV003483685	SCV004228865	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-26-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.