ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1568A>G (p.His523Arg) (rs80358443)

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Total submissions: 13
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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 In silico models in agreement (benign);Other data supporting benign classification
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 and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc 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 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 RCV000590104 SCV000888982 likely benign not provided 2018-03-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590104 SCV001500573 likely benign not provided 2020-11-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082887 SCV000114961 likely benign Breast-ovarian cancer, familial 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.

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