ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9592T>C (p.Cys3198Arg) (rs80359229)

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Total submissions: 15
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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) RCV000031835 SCV000244495 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 = 0.00000368
Invitae RCV000045863 SCV000073876 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163019 SCV000213507 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.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000045863 SCV000267850 likely benign Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000031835 SCV000487886 benign Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000421898 SCV000517305 likely benign not specified 2017-10-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000163019 SCV000684076 likely benign Hereditary cancer-predisposing syndrome 2015-07-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000421898 SCV000695255 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9592T>C (p.Cys3198Arg) 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 6.4e-05 in 251414 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00013 vs 0.00075), allowing no conclusion about variant significance. c.9592T>C has been reported in the literature in individuals affected with or at risk of breast cancer and lung adenocarcinoma (e.g. Lu_2012, Parry_2017) but it was also reported in non-cancer individuals (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants in the same gene have been reported in multiple cases (BRCA2 c.748delG, p.Val250Xfs; BRCA2 c.5863delT, p.Ser1955GlnfsX8; BRCA2 c.4965C>G, p.Tyr1655X; BIC database and Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign while one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587762 SCV000885108 benign not provided 2017-07-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587762 SCV000887971 benign not provided 2018-08-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001110895 SCV001268383 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.
Illumina Clinical Services Laboratory,Illumina RCV000031835 SCV001268384 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.
Baylor Genetics RCV000031835 SCV001482972 uncertain significance Breast-ovarian cancer, familial 2 2019-01-14 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sharing Clinical Reports Project (SCRP) RCV000031835 SCV000054443 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031835 SCV000147671 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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