Submissions for variant NM_000059.4(BRCA2):c.4159T>A (p.Leu1387Ile)

gnomAD frequency: 0.00001  dbSNP: rs431825317

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164638	SCV000215302	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-11	criteria provided, single submitter	clinical testing	The p.L1387I variant (also known as c.4159T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 4159. The leucine at codon 1387 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in 1 of 860 individuals with a personal history of breast cancer (Stella S et al. Genes (Basel), 2024 Jul;15:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998218	SCV000600578	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	The BRCA2 c.4159T>A (p.Leu1387Ile) variant has been reported in a large case-control study, this variant has been reported in at least one individual with breast cancer and none of the unaffected controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been observed in an individual undergoing multigene panel testing due to personal or family history of cancer (PMID: 31853058 (2020)). A multifactorial analysis study has characterized the variant as being likely benign (PMID: 31131967 (2019)). In addition, the variant has also been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000042 (1/238866 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637472	SCV000758932	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1387 of the BRCA2 protein (p.Leu1387Ile). This variant is present in population databases (rs431825317, 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: 96804). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164638	SCV003848732	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).
Color Diagnostics, LLC DBA Color Health	RCV000164638	SCV004362036	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1387 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A multi-factorial analysis classifies this variant as likely benign (PMID: 31131967). This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008160). This variant has been identified in 1/238866 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.
All of Us Research Program, National Institutes of Health	RCV004804083	SCV004845277	uncertain significance	BRCA2-related cancer predisposition	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1387 of the BRCA2 protein. Computational prediction 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. A multi-factorial analysis classifies this variant as likely benign (PMID: 31131967). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/238866 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000637472	SCV005688855	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing	The missense variant NM_000059.4(BRCA2):c.4159T>A (p.Leu1387Ile) has not been reported previously as a pathogenic variant to our knowledge. There is a small physicochemical difference between leucine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The gene BRCA2 contains 150 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000082925	SCV000114999	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing