ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5144T>G (p.Leu1715Trp)

dbSNP: rs1064793634
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486142 SCV000566654 uncertain significance not provided 2015-05-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5144T>G at the cDNA level, p.Leu1715Trp (L1715W) at the protein level, and results in the change of a Leucine to a Tryptophan (TTG>TGG). Using alternate nomenclature, this variant would be defined as BRCA2 5372T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1715Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Tryptophan differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu1715Trp occurs at a position that is not conserved and is located in the BRC repeats region that interacts with RAD51 (Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Leu1715Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002526537 SCV003339083 uncertain significance Hereditary breast ovarian cancer syndrome 2022-04-11 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 419087). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 1715 of the BRCA2 protein (p.Leu1715Trp).
University of Washington Department of Laboratory Medicine, University of Washington RCV003157570 SCV003847030 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).

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