ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2663A>T (p.His888Leu)

dbSNP: rs876658843
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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 RCV000562208 SCV000668475 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing The p.H888L variant (also known as c.2663A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2663. The histidine at codon 888 is replaced by leucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001226311 SCV001398622 uncertain significance Hereditary breast ovarian cancer syndrome 2020-12-20 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 482938). This sequence change replaces histidine with leucine at codon 888 of the BRCA1 protein (p.His888Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000562208 SCV003851000 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).
MGZ Medical Genetics Center RCV003607318 SCV004543932 likely benign Familial cancer of breast 2024-02-09 criteria provided, single submitter clinical testing ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP

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