ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2981G>T (p.Cys994Phe)

dbSNP: rs1238452758
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000812262 SCV000952570 uncertain significance Hereditary breast ovarian cancer syndrome 2021-07-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 994 of the BRCA1 protein (p.Cys994Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA1-related disease. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV002440758 SCV002746295 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-15 criteria provided, single submitter clinical testing The p.C994F variant (also known as c.2981G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2981. The cysteine at codon 994 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002440758 SCV003849214 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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