Submissions for variant NM_000059.4(BRCA2):c.1568A>G (p.His523Arg)

gnomAD frequency: 0.00009  dbSNP: rs80358443

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132044	SCV000187104	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000590104	SCV000210563	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14973102, 22126563, 26852015, 19656164, 27124784, 28222693, 27257965, 32879886, 30415210, 30702160, 32211327, 32455662, 31825140)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240762	SCV000265928	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Invitae	RCV001088277	SCV000283170	benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132044	SCV000537501	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000082887	SCV000575722	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160205	SCV000694546	benign	not specified	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1568A>G (p.His523Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 246858 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1568A>G has been reported in the literature predominantly among individuals of East Asian ancestry affected with Hereditary Breast and Ovarian Cancer (Cao_2016, Coulet_2010, Dong_2015, Coulet_2010, Park_2016,Seong_2009, Suter_2004, Zhong_2011, Zhong_2016, Bhaskaran_2019, Dong_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the literature as well as our own laboratory (BRCA2 c.2175dup, p.Val726fs (Dong_2015); BRCA1 c.5521delA, p.Ser1841fs (Dong_2018); and our laboratory, BRCA1 c.3770_3771delAG, p.Glu1257fsX9), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments predominantly as likely benign/benign (Benign, n=1; Likely benign, n=6; uncertain significance, n=2). At-least one submitter has downgraded this variant from its previous classification of Likely benign to Benign. Based on the evidence outlined above, the variant was re-classified as benign.
3DMed Clinical Laboratory Inc	RCV000240762	SCV000804016	likely benign	Breast neoplasm	2018-05-21	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677856	SCV000804017	likely benign	Cancer of the pancreas	2018-05-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160205	SCV000888982	benign	not specified	2021-04-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132044	SCV002533241	likely benign	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160205	SCV002550282	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153359	SCV003843829	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132044	SCV003851494	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000082887	SCV000114961	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353673	SCV000591754	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His523Arg variant was identified in 4 of 2740 proband chromosomes (frequency: 0.001) from Chinese and Korean individuals or families with breast cancer, benign breast disease and ESCC (esophageal squamous cell cancer), and was identified in 2 of 1168 control chromosomes (frequency: 0.002) from healthy individuals (Cao 2016, Seong M-W 2009, Suter 2004, Zhong 2011). The variant was (also) identified by our laboratory in 1 Chinese individual with breast cancer. The variant was also identified in dbSNP (ID: rs80358443) “With Likely benign/Uncertain significance allele”, Clinvitae database (classification likely benign), the ClinVar database (classification likely benign, submitters: Ambry Genetics, GeneDx, SCRP (Sharing Clinical Reports Project), derived from Myriad reports), GeneInsight COGR database (unclassified “by a clinical laboratory”), and UMD (2X as an ”unclassified variant”). It was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 13 of 8636 chromosomes (frequency: 0.0015) from a population of East Asians, and in 2 of 16334 (frequency: 0.0001) in a South Asian population. In EXAC, it was not seen in the European (Non-Finnish), Other, African, Latino and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.His523 residue is not conserved in mammals, (with Ser, Cys and Asn present) and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250558	SCV002520937	likely benign	Familial cancer of breast		no assertion criteria provided	literature only