ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9460C>T (p.His3154Tyr)

dbSNP: rs760189451
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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 RCV000637711 SCV000759184 uncertain significance Hereditary breast ovarian cancer syndrome 2017-12-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 3154 of the BRCA2 protein (p.His3154Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs760189451, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001019374 SCV001180722 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-18 criteria provided, single submitter clinical testing The p.H3154Y variant (also known as c.9460C>T), located in coding exon 24 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9460. The histidine at codon 3154 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV004788069 SCV005402403 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2024-02-24 criteria provided, single submitter clinical testing The BRCA2 c.9460C>T (p.His3154Tyr) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with BRCA2-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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