ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.53G>A (p.Arg18His) (rs80358762)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077351 SCV000244457 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00035
Invitae RCV000044652 SCV000072665 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162817 SCV000213300 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Counsyl RCV000077351 SCV000220763 likely benign Breast-ovarian cancer, familial 2 2014-10-02 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508439 SCV000600639 likely benign not specified 2017-05-01 criteria provided, single submitter clinical testing
Color RCV000162817 SCV000683702 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
GeneDx RCV000508439 SCV000730487 likely benign not specified 2017-07-25 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 RCV000508439 SCV000916827 likely benign not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.53G>A (p.Arg18His) results in a non-conservative amino acid change in 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 2.4e-05 in 251948 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, the variant allele is also reported in databases specific to Japanese individuals at a frequency of 0.0043 (HGVD-Kyoto, jMorp). The observed variant frequency within Japanese individuals in these databases is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00075), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.53G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, prostate cancer and pancreatic ductal adenocarcinoma (e.g. Han_2006, Spurdle_2008, Hayano_2016, Park_2017, Choi_2018, Nakagomi_2018, Takeuchi_2018, So_2019, Terashima_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (e.g. BRCA1 c.3715_3717delTCTinsC, p.Ser1239Profs; BRCA2 c.5237_5238dup, p.Asn1747LeufsX31), providing further supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a homology directed repair (HDR) assay demonstrated the variant retained normal function (e.g. Xia_2006, Mesman_2019). Five ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000077351 SCV000109148 likely benign Breast-ovarian cancer, familial 2 2010-08-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077351 SCV000146077 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing

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