ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5752C>T (p.His1918Tyr) (rs80358803)

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Total submissions: 17
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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) RCV000077359 SCV000244460 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 = 0.00000575
Invitae RCV001081769 SCV000072756 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000044743 SCV000210619 likely benign not provided 2019-04-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016).; This variant is associated with the following publications: (PMID: 23704879, 24323938, 17924331, 21990134, 28866612)
Ambry Genetics RCV000163008 SCV000213496 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 RCV000077359 SCV000220254 likely benign Breast-ovarian cancer, familial 2 2014-04-17 criteria provided, single submitter literature only
PreventionGenetics,PreventionGenetics RCV000168582 SCV000301766 likely benign not specified criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000168582 SCV000593719 likely benign not specified 2016-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044743 SCV000600662 benign not provided 2018-09-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168582 SCV000694899 likely benign not specified 2019-04-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5752C>T (p.His1918Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251154 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.5752C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and also, prostate cancer (Ernst_2018, Lu_2015, Kote-Jarai_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (LabCorp; BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. In addition, studies utilizing multifactorial likelihood models to assess the clinical significance of BRCA2 variants predict this variant to be neutral/not pathogenic (Lindor_2012, Easton_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters including one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all have classified the variant as benign (n=2)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign until additional clinical and functional data become available.
Color Health, Inc RCV000163008 SCV000910732 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168582 SCV000966583 uncertain significance not specified 2018-05-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Illumina Clinical Services Laboratory,Illumina RCV000077359 SCV001267162 uncertain significance Breast-ovarian cancer, familial 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001110578 SCV001268030 uncertain significance Fanconi anemia, complementation group D1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Research and Development, ARUP Laboratories RCV001646432 SCV001854855 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) RCV000077359 SCV000109156 likely benign Breast-ovarian cancer, familial 2 2011-02-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077359 SCV000146689 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168582 SCV000591998 benign not specified no assertion criteria provided clinical testing The BRCA2 p.His1918Tyr variant was identified dbSNP (ID: rs80358803) “With likely benign allele”, Clinvitae database (as “likely benign”), LOVD (as “predicted neutral”), ARUP Laboratories BRCA Mutations Database (as “not pathogenic”), the ClinVar database (classified as a benign variant reviewed by an expert panel), GeneInsight COGR database (classified 2X as “likely benign” 1X as “benign” and 1X “unclassified” ), the BIC database (9X with unknown clinical importance), and UMD (1X as an unknown variant). The variant was also identified by the Exome Aggregation Consortium (ExAC) database in 5 of 66606 (European (Non-Finnish)) alleles (frequency: 7.51X10-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was found in the literature, classified by several functional and in silico studies as benign (Easton 2007, Lindor 2012, Guidugli 2014).The p.His1918 residue is not conserved in mammals 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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