Submissions for variant NM_000059.4(BRCA2):c.6792G>C (p.Leu2264Phe)

gnomAD frequency: 0.00001  dbSNP: rs756182263

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239333	SCV000296551	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358732	SCV001554577	uncertain significance	not specified	2021-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6792G>C (p.Leu2264Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250872 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6792G>C has been reported in the literature in at-least one individual affected with MMR (mismatch repair) proficient colorectal cancer (example, Pearlman_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854914	SCV002234568	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2264 of the BRCA2 protein (p.Leu2264Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 252417). 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	RCV002365248	SCV002663777	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	The p.L2264F variant (also known as c.6792G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6792. The leucine at codon 2264 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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	RCV002365248	SCV003847456	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).