Submissions for variant NM_000059.4(BRCA2):c.53G>A (p.Arg18His)

gnomAD frequency: 0.00001  dbSNP: rs80358762

Total submissions: 11

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, susceptibility to, 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 ovarian cancer syndrome	2023-12-18	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, susceptibility to, 2	2014-10-02	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703945	SCV000600639	likely benign	not provided	2023-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
Sema4, Sema4	RCV000162817	SCV002536131	likely benign	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000077351	SCV000109148	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-08-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077351	SCV000146077	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing