Submissions for variant NM_000059.4(BRCA2):c.2719A>G (p.Lys907Glu)

dbSNP: rs876659600

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216812	SCV000276235	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-18	criteria provided, single submitter	clinical testing	The p.K907E variant (also known as c.2719A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2719. The lysine at codon 907 is replaced by glutamic acid, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital	RCV000656469	SCV000778339	uncertain significance	Breast cancer, susceptibility to	2018-03-25	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809060	SCV000949198	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 907 of the BRCA2 protein (p.Lys907Glu). 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: 232177). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216812	SCV003850089	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).
GeneDx	RCV003328569	SCV004035732	uncertain significance	not provided	2023-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2947A>G; This variant is associated with the following publications: (PMID: 25348012, 31853058, 30287823, 31131967, 29884841, 32377563, 32467295)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586634	SCV005076595	uncertain significance	not specified	2024-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2719A>G (p.Lys907Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-06 in 345874 control chromosomes, including case-control studies (gnomAD, Guo_2020, Okawa_2023, Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2719A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31837001, 30287823, 36243179). ClinVar contains an entry for this variant (Variation ID: 232177). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004804899	SCV005424343	uncertain significance	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 907 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, but has been reported in unaffected individuals (PMID: 30287823, 32980694, 36243179). 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.