ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8834A>G (p.Gln2945Arg) (rs587781800)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130065 SCV000184892 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000410010 SCV000488645 uncertain significance Breast-ovarian cancer, familial 2 2016-05-12 criteria provided, single submitter clinical testing
Invitae RCV000462799 SCV000549685 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2945 of the BRCA2 protein (p.Gln2945Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs587781800, ExAC 0.002%). This variant has been observed in an individual with a family history of breast cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA1, which suggests that this c.8834A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 141506). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000487119 SCV000570593 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8834A>G at the cDNA level, p.Gln2945Arg (Q2945R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 9062A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln2945Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2945Arg occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). 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 Gln2945Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130065 SCV000906694 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing

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