ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
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 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162817 SCV000213300 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Health, Inc RCV000162817 SCV000683702 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
GeneDx RCV001703945 SCV000730487 likely benign not provided 2019-11-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21990134, 24323938, 16949048, 27701467, 17100994, 18375895, 21702907, 25017803, 29215753, 30415210, 29988080, 28111427, 29929473, 29240602, 29176636, 16793542, 29802286, 32444794)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508439 SCV000916827 benign not specified 2021-07-31 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 with classifications ranging from VUS to likely benign 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. Multiple co-occurrences with pathogenic variants have been reported in databases and literature (e.g. BIC database-BRCA1 c.3715_3717delTCTinsC, p.Ser1239Profs; KConfab database-BRCA2 c.5237_5238dup, p.Asn1747LeufsX31; Jia_2018-MLH1 c.1852_1854delAAG , p.K618del), providing further supporting evidence for a benign role. This is consistent with multifactorial probability models that report a neutral outcome (Lindor_2012). 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 benign.
Research and Development, ARUP Laboratories RCV001646394 SCV001854314 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.