ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2355A>C (p.Leu785Phe)

dbSNP: rs1567795966
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773754 SCV000907454 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773754 SCV001175929 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-04 criteria provided, single submitter clinical testing The p.L785F variant (also known as c.2355A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2355. The leucine at codon 785 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well 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.
Invitae RCV001210889 SCV001382398 uncertain significance Hereditary breast ovarian cancer syndrome 2022-02-10 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 785 of the BRCA1 protein (p.Leu785Phe). 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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 629066). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290640 SCV001478758 uncertain significance not specified 2021-01-29 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2355A>C (p.Leu785Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250624 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.2355A>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000773754 SCV003847733 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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