ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2810A>C (p.Gln937Pro) (rs730881516)

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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 RCV000509647 SCV000608043 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000509647 SCV000906051 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000160050 SCV000210292 uncertain significance not provided 2017-06-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2810A>C at the cDNA level, p.Gln937Pro (Q937P) at the protein level, and results in the change of a Glutamine to a Proline (CAA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 3038A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln937Pro was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gln937Pro occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln937Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000466542 SCV000549812 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 937 of the BRCA2 protein (p.Gln937Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182191). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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