Submissions for variant NM_000059.4(BRCA2):c.5900A>T (p.Lys1967Met)

dbSNP: rs959089047

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458121	SCV000549848	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1967 of the BRCA2 protein (p.Lys1967Met). This variant is not present in population databases (gnomAD no frequency). 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: 409590). 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 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.
Ambry Genetics	RCV000561855	SCV000661274	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.K1967M variant (also known as c.5900A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5900. The lysine at codon 1967 is replaced by methionine, an amino acid with similar properties. This alteration has not been reported in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.00008 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). Additionally, this alteration has not been reported in 7636 unselected prostate cancer patients and was observed with an allele frequency of 0.00008 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561855	SCV003850763	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).
All of Us Research Program, National Institutes of Health	RCV004802011	SCV005424507	uncertain significance	BRCA2-related cancer predisposition	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with methionine at codon 1967 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related cancer in the literature, but has been reported in an unaffected individual (PMID: 30287823, 31214711, 32980694). 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.