ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2280A>C (p.Leu760Phe)

dbSNP: rs1593896537
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000816378 SCV000956883 uncertain significance Hereditary breast ovarian cancer syndrome 2022-10-11 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: 659381). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 760 of the BRCA2 protein (p.Leu760Phe).
Color Diagnostics, LLC DBA Color Health RCV001186346 SCV001352739 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-06 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 760 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 individuals affected with breast cancer and in unaffected individuals in the same study (PMID: 30287823). This variant has not been identified 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001186346 SCV003848193 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004702451 SCV005203450 uncertain significance not specified 2024-07-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2280A>C (p.Leu760Phe) 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 1.7e-05 in 1736714 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.2280A>C has been reported in the literature in individuals affected withbreast cancer as well as in healthy controls (e.g. Okawa_2023, Momozawa_2018). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 36243179). ClinVar contains an entry for this variant (Variation ID: 659381). Based on the evidence outlined above, the variant was classified as uncertain significance.

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