ClinVar Miner

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

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Total submissions: 8
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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 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 2019-11-13 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 2020-02-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410010 SCV001270517 uncertain significance Breast-ovarian cancer, familial 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001112819 SCV001270518 uncertain significance Fanconi anemia, complementation group D1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Integrated Genetics/Laboratory Corporation of America RCV001193118 SCV001361751 uncertain significance not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8834A>G (p.Gln2945Arg) results in a conservative amino acid change located in the OB2 domain (Yang_2002) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250798 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8834A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.4183C>T (p.Gln1395X) from UMD database; an unspecified BRCA1 variant from a clinical diagnostic laboratory), providing supporting evidence for a benign role. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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