ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1662T>G (p.Cys554Trp) (rs80358451)

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Total submissions: 14
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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) RCV000077261 SCV000244423 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 = 0.000000396
Invitae RCV000167777 SCV000071869 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000043856 SCV000210566 likely benign not specified 2017-05-09 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.
Ambry Genetics RCV000163000 SCV000213488 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768621 SCV000219304 uncertain significance Breast and/or ovarian cancer 2015-10-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043856 SCV000591759 benign not specified 2015-12-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282621 SCV000602785 benign none provided 2019-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043856 SCV000694555 benign not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1662T>G (p.Cys554Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 282630 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.7e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.1662T>G has been reported in the literature in individuals affected with prostate cancer, breast cancer and ovarian cancer without strong evidence for causality (Kote-Jari_2011, Ganguly_1998, Ganguly_1997). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two studies using multifactorial likelihood models have classified this variant as having a neutral impact (Easton_2007, Lindor_2012) (IARC class I). In addition, although a functional study (Mondal_2012) reports this variant as resulting in increased cytokinetic defects through a disruption of BRCA2 interactions with other proteins, the authors do not report its effect on BRCA2 dependant homologous recombination repair. Therefore, the impact of this study on the pathophysiology and mechanism of cancer has not been fully understood and/or established. At least one co-occurrence of this variant with another likely pathogenic variant has been reported at our laboratory (BRCA2 c.4305_4309delTATTA, p.Asn1435fsX8), providing supporting evidence for a benign role. Nine submitters including one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014, some citing overlapping evidence utilized in the context of this evaluation. Eight submitters including the expert panel have classified the variant as benign (n=5)/likely benign(n=3) while one retains the classification as a VUS. We have followed this variant for over 6 years since its initial identification at our laboratory. Based on the lack on conclusive evidence supporting a pathogenic outcome for this variant in literature spanning over two decades as ascertained above and the emerging majority consensus in the field, the variant was re-classified as benign.
Color Health, Inc RCV000163000 SCV000910758 benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Mendelics RCV000077261 SCV001139005 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077261 SCV000109058 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077261 SCV000145909 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148416 SCV000190115 likely benign Carcinoma of male breast 2014-06-01 no assertion criteria provided research
True Health Diagnostics RCV000163000 SCV000886672 likely benign Hereditary cancer-predisposing syndrome 2018-11-12 no assertion criteria provided clinical testing

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