ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7505G>A (p.Arg2502His) (rs56070345)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588836 SCV000602788 likely benign not provided 2018-04-16 criteria provided, single submitter clinical testing The BRCA2 c.7505G>A; p.Arg2502His variant (rs56070345) is reported in patients with breast and ovarian cancer (Akbari 2011, Gayther 1999, Spearman 2008), but also in an unaffected individual (Balabanski 2014). This variant is reported in ClinVar (Variation ID: 52345) and found in the general population with an overall allele frequency of 0.007% (17/246182 alleles) in the Genome Aggregation Database. The arginine at codon 2502 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, this variant has been previously identified by our laboratory in a patient who also carries a pathogenic truncating BRCA1 variant. Based on available information, this variant is considered to be likely benign. REFERENCES Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6. Balabanski L et al. Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. Mol Clin Oncol. 2014 May;2(3):435-439. Gayther SA et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet. 1999 Oct;65(4):1021-9. Spearman AD et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008 Nov 20;26(33):5393-400.
Ambry Genetics RCV000131692 SCV000186728 benign Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown),Other strong data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000083136 SCV000147109 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000131692 SCV000902828 benign Hereditary cancer-predisposing syndrome 2015-12-29 criteria provided, single submitter clinical testing
Counsyl RCV000083136 SCV000784917 uncertain significance Breast-ovarian cancer, familial 2 2017-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000045234 SCV000210652 likely benign not specified 2017-10-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000588836 SCV000695072 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing Variant summary: This c.7505G>A affects a not conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to be benign. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. An in vitro study also showed that this variant does not affect splicing. This variant was found in 11/122080 control chromosomes at a frequency of 0.0000901, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007503) in this gene. However, it may still represent as a rare polymorphism. This variant has been reported in multiple HBOC patients/families but without strong evidence for or against pathogenicity. Probability-based models hint for a non-pathogenicity, however, they are not definite. Two reputable databases report this variant as having uncertain significance, however more recent classifications by multiple labs are in benign spectrum. Taken together, the variant was classified as a VUS-possibly benign until additional information becomes available.
Invitae RCV000195335 SCV000073247 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-20 criteria provided, single submitter clinical testing
PreventionGenetics RCV000588836 SCV000805764 likely benign not provided 2017-10-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083136 SCV000115210 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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