ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7682A>G (p.Gln2561Arg) (rs55647716)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217467 SCV000278182 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000217467 SCV000905501 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Counsyl RCV000412336 SCV000488807 uncertain significance Breast-ovarian cancer, familial 2 2016-06-21 criteria provided, single submitter clinical testing
GeneDx RCV000590423 SCV000566290 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7682A>G at the cDNA level, p.Gln2561Arg (Q2561R) 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 7910A>G. This variant has not, to our knowledge, been published in the literatureas pathogenic or benign. BRCA2 Gln2561Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2561Arg occurs at a position that is not conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gln2561Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590423 SCV000695093 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7682A>G (p.Gln2561Arg) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 2/121276 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in a head and neck squamous cell carcinoma sample as a germline variant without clear evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000195904 SCV000254211 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2561 of the BRCA2 protein (p.Gln2561Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs55647716, ExAC 0.02%). This variant has been reported in an individual affected with head and neck squamous cell carcinoma (PMID: 26689913), and in an individual affected with pancreatic cancer (PMID: 28767289, 29309945). ClinVar contains an entry for this variant (Variation ID: 216258). 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 arginine 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 RCV000590423 SCV000887921 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing

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