ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5191C>T (p.His1731Tyr) (rs80358745)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566864 SCV000673073 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000637528 SCV000758991 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1731 of the BRCA2 protein (p.His1731Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs80358745, ExAC 0.002%). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 20104584, 28263838) and in a family with predisposition to breast and/or ovarian cancer that also carried a pathogenic variant, suggesting that this c.5191C>T variant was not the primary cause of disease. However, the pathogenic variant was not formally identified in the report (PMID: 27062684). This variant is also known as 5419C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 252409). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239258 SCV000296516 uncertain significance Breast-ovarian cancer, familial 2 2016-04-02 criteria provided, single submitter clinical testing

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