ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7786G>A (p.Gly2596Arg) (rs398122591)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160142 SCV000210447 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7786G>A at the cDNA level, p.Gly2596Arg (G2596R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant, also known as 8014G>A using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2596Arg was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2596Arg occurs at a position that is conserved across species and is located within 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 information, it is unclear whether BRCA2 Gly2596Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000197789 SCV000254212 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-02-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2596 of the BRCA2 protein (p.Gly2596Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs398122591, ExAC 0.001%). This variant has been reported in the Leiden Open-source Variation Database, in an individual affected with breast cancer (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91492). A different nucleotide change (c.7786G>C) resulting in the same missense change (p.Gly2596Arg) has been reported to affect BRCA2 protein function (PMID: 29884841). 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 RCV000160142 SCV000296520 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing
Counsyl RCV000077009 SCV000489011 uncertain significance Breast-ovarian cancer, familial 2 2016-08-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509715 SCV000608032 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.G2596R variant (also known as c.7786G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7786. The glycine at codon 2596 is replaced by arginine, an amino acid with dissimilar properties. Two separate homology-directed DNA repair (HDR) assays have demonstrated p.G2596R is non-functional (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000509715 SCV000683904 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770731 SCV000902212 uncertain significance Breast and/or ovarian cancer 2017-05-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000197789 SCV001623182 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-04-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7786G>A (p.Gly2596Arg) results in a non-conservative amino acid change located in the breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251378 control chromosomes. c.7786G>A has been reported in the literature as a VUS in at-least one individual affected with male breast cancer (Rizzolo_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal homology directed repair (HDR) activity and a non-functional impact using a well-established mouse embryonic stem cell based assay (example, Biswas_2020, Guidugli_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6). At-least one submitter reports a likely pathogenic classiciation using overlapping functional evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077009 SCV000108806 uncertain significance Breast-ovarian cancer, familial 2 2010-03-23 no assertion criteria provided clinical testing

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