ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4905G>T (p.Leu1635Phe)

dbSNP: rs397507342
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000461109 SCV000549634 uncertain significance Hereditary breast ovarian cancer syndrome 2025-01-23 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 1635 of the BRCA2 protein (p.Leu1635Phe). This variant is present in population databases (rs397507342, gnomAD 0.0009%). This missense change has been observed in individual(s) with liver hepatocellular carcinoma (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 37930). 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.
Color Diagnostics, LLC DBA Color Health RCV000581537 SCV000688904 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 1635 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 been reported in an individual affected with liver cancer (PMID: 29625052). This variant has been identified in 1/248988 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.
Counsyl RCV000031511 SCV000785470 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2017-08-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581537 SCV001185091 likely benign Hereditary cancer-predisposing syndrome 2024-03-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
University of Washington Department of Laboratory Medicine, University of Washington RCV000581537 SCV003852192 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 RCV004803037 SCV004845747 uncertain significance BRCA2-related cancer predisposition 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 1635 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 hereditary cancer in the literature. This variant has been identified in 1/248988 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.
Sharing Clinical Reports Project (SCRP) RCV000031511 SCV000054116 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2013-02-04 no assertion criteria provided clinical testing

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