ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4372C>T (p.His1458Tyr) (rs80358672)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044399 SCV000072412 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1458 of the BRCA2 protein (p.His1458Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs80358672, ExAC 0.01%). This variant has been observed in individuals affected with breast cancer in the literature (PMID: 27221885) and the Leiden Open-source Variation Database (PMID: 21520333). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.4372C>T variant was not the primary cause of disease. This variant is also known as c.4600T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 51636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000216745 SCV000273069 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000480609 SCV000570720 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4372C>T at the cDNA level, p.His1458Tyr (H1458Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). Using alternate nomenclature, this variant has been previously published as BRCA2 4600C>T. This variant was observed in at least one individual with familial breast cancer (Anwar 2016). BRCA2 His1458Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the binding domains with RAD51 and POLH (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His1458Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000216745 SCV000683613 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077323 SCV000109120 uncertain significance Breast-ovarian cancer, familial 2 2010-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077323 SCV000146414 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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