ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6751C>T (p.His2251Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1260385979
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000795503 SCV000934968 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 2251 of the BRCA2 protein (p.His2251Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 642108). 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 with a negative predictive value of 95%. 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.
Ambry Genetics RCV001025612 SCV001187837 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-14 criteria provided, single submitter clinical testing The p.H2251Y variant (also known as c.6751C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6751. The histidine at codon 2251 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001025612 SCV003847423 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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