Submissions for variant NM_000059.4(BRCA2):c.4070T>G (p.Leu1357Arg)

dbSNP: rs55796504

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130026	SCV000184852	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The p.L1357R variant (also known as c.4070T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 4070. The leucine at codon 1357 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
GeneDx	RCV000160072	SCV000210328	uncertain significance	not provided	2017-07-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4070T>G at the cDNA level, p.Leu1357Arg (L1357R) at the protein level, and results in the change of a Leucine to an Arginine (CTA>CGA). Using alternate nomenclature, this variant would be defined as BRCA2 4298T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1357Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu1357Arg occurs at a position that is not conserved and is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, it is unclear whether BRCA2 Leu1357Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000409740	SCV000488012	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462928	SCV000549580	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1357 of the BRCA2 protein (p.Leu1357Arg). This variant is present in population databases (rs55796504, 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: 141478). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130026	SCV000683599	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1357 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/247396 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781066	SCV000918870	uncertain significance	not specified	2021-06-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4070T>G (p.Leu1357Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 247396 control chromosomes. 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.4070T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160072	SCV001133779	uncertain significance	not provided	2022-10-14	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/247396 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798438	SCV002043022	uncertain significance	Breast and/or ovarian cancer	2019-12-24	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130026	SCV003848653	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	RCV000409740	SCV004845266	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-30	criteria provided, single submitter	clinical testing