ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.817A>C (p.Met273Leu)

dbSNP: rs587781797
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130060 SCV000184887 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-25 criteria provided, single submitter clinical testing The p.M273L variant (also known as c.817A>C), located in coding exon 6 of the BRIP1 gene, results from an A to C substitution at nucleotide position 817. The methionine at codon 273 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved on sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000130060 SCV000910005 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-26 criteria provided, single submitter clinical testing This missense variant replaces methionine with leucine at codon 273 of the BRIP1 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 1/251048 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000804460 SCV000944371 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 273 of the BRIP1 protein (p.Met273Leu). This variant is present in population databases (rs587781797, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141503). 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 expected to disrupt BRIP1 protein function with a positive predictive value of 80%. 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.
GeneDx RCV001753514 SCV002006720 uncertain significance not provided 2019-12-13 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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