ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4527A>C (p.Gln1509His) (rs56283738)

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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 RCV000215274 SCV000276392 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000487203 SCV000566079 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4527A>C at the cDNA level, p.Gln1509His (Q1509H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAC). Using alternate nomenclature, this variant would be defined as BRCA2 4755A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln1509His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln1509His is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Gln1509His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204087 SCV000261197 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 1509 of the BRCA2 protein (p.Gln1509His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs56283738, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 220561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The histidine 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 RCV000238908 SCV000296538 uncertain significance Breast-ovarian cancer, familial 2 2016-04-08 criteria provided, single submitter clinical testing

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