ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000588836 SCV000073247 likely benign not provided 2019-02-22 criteria provided, single submitter clinical testing
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
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.
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.
Integrated Genetics/Laboratory Corporation of America RCV000045234 SCV000695072 likely benign not specified 2019-08-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7505G>A (p.Arg2502His) results in a non-conservative amino acid change located in the helical domain (IPR015252) 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 6.4e-05 in 252472 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than the expected maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (HBOC) (0.00075), allowing no conclusion about variant significance. The variant has been reported in the literature in individuals affected with breast- or ovarian cancer (e.g. Akbari_2011, Gayther_1999, Spearman_2008, Bolognesi_2014, Cunningham_2014, Davies_2018, Kraus_2016, Momozawa_2018), but also in controls (Bolognesi_2014, Balabanski_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other BRCA1 pathogenic variants have been reported (c.5096G>A (p.Arg1699Gln) in UMD; c.68_69delAG in an LCA internal sample, and a not specified truncating variant in a ClinVar submission), providing supporting evidence for a benign role. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect on splicing (Houdayer_2012), and no effect on the BRCA2/DSS1 interaction (Caleca_2019). Seven other ClinVar submissions (evaluation after 2014) classified the variant as VUS (1x), likely benign (4x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000083136 SCV000784917 uncertain significance Breast-ovarian cancer, familial 2 2017-02-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588836 SCV000805764 likely benign not provided 2017-10-19 criteria provided, single submitter clinical testing
Color RCV000131692 SCV000902828 benign Hereditary cancer-predisposing syndrome 2015-12-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588836 SCV001133901 likely benign not provided 2018-08-09 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000083136 SCV000147109 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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