ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7504C>T (p.Arg2502Cys) (rs55716624)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045233 SCV000073246 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000168602 SCV000108638 likely benign not specified 2018-01-30 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 RCV000131136 SCV000186071 benign Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
CSER _CC_NCGL, University of Washington RCV000148436 SCV000190135 uncertain significance Breast and/or ovarian cancer 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000034459 SCV000226200 uncertain significance not provided 2014-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034459 SCV000296686 benign not provided 2018-08-03 criteria provided, single submitter clinical testing
Counsyl RCV000077403 SCV000488326 uncertain significance Breast-ovarian cancer, familial 2 2016-04-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168602 SCV000538498 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency; ClinVar: 2 LB, 7 VUS
Genetic Services Laboratory, University of Chicago RCV000168602 SCV000593754 likely benign not specified 2017-07-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034459 SCV000695071 benign not provided 2016-02-11 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/5 in silico tools predict the variant to be benign. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.029%. It is most prevalent in the African subpopulation with an observed allele frequency of 0.29% which exceeds the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%) indicating the variant to be benign. The variant was also observed in HBOC spectrum patients, however without strong evidence for pathogenicity. A functional study reported the variant not to have an effect on normal splicing. Moreover, BIC reports co-occurrence with multiple pathogenic BRCA1 variants c.3764_3765insA (p.Asn1255fsX12), and c.5324T>G (p.Met1775Arg) and c. 5074G>A (p.Asp1692Asn) further supporting a benign impact. Clinical diagnostic centers classify variant as Uncertain/Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.
Mendelics RCV000045233 SCV000838854 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168602 SCV000883514 likely benign not specified 2019-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131136 SCV000902720 benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Mendelics RCV000077403 SCV001139183 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000045233 SCV001450728 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing The BRCA2 c.7504C>T (p.Arg2502Cys) missense change has a maximum subpopulation frequency of 0.32% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32930633-C-T). This frequency is higher than would be expected for a pathogenic variant in BRCA2 (BS1; PMID: 28166811). This variant affects a nucleotide that is not highly conserved and is predicted to be benign by multiple in silico algorithms (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4.
Research and Development, ARUP Laboratories RCV001642547 SCV001854929 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034459 SCV000043226 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077403 SCV000109200 uncertain significance Breast-ovarian cancer, familial 2 2007-02-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077403 SCV000147108 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 RCV000034459 SCV000592116 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 p.Arg2502Cys variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0.001) from individuals or families with cancer syndromes (Johnston 2012). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs55716624 “With Uncertain significance allele”, with a minor allele frequency of 0.0004 (2/5000 chromosomes tested in 1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server) in 15 of 4406 African Americans (frequency: 0.0034) and not found in European Americans, Exome Aggregation Consortium database (March 14, 2016) in 36 of 121024 chromosomes (frequency:0.003) from a population of African (30/10322), European (Non-Finnish-4/66524), Latino (1/11538) individuals and not in East Asian , South Asian and European (Finnish) or Other individuals. The p.Arg2502Cys variant was also identified in HGMD, LOVD (2x as unknown), classified as an Uncertain significance variant by 6 separate submitters to the ClinVar database (the Sharing Clinical Reports Project derived from Myriad reports, GeneDX, BIC, Ambry Genetics, CSER_CC_NCGL, Biesecker Laboratory – ClinSeq Project_NHGRI), GeneInsight COGR 1x (classified as uncertain by a clinical laboratory), the BIC database (17x with unknown clinical importance), and UMD (6x as an uncertain variant). Note the variant co-occurred 2x with 2 other variants of unknown significance i.e. c.1798T>C, p.Tyr600His VUS and c.IVS10+9delGT VUS. The p.Arg2502 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Arg2502Cys 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 addition, an assessment of 1,433 missense variants of unknown clinical significance, a likelihood ratio was computed based on a hypothesis that the variants were equivalent to an average deleterious mutation compared with neutral with respect to odds risk to other factors such as family history and co-occurrence. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. The combined odds ratio for the variant was 21:1 and predicted causal, an odds ratio of 100:1 being neutral (Easton 2007). In another study (Karchin 2008), the authors are in disagreement with the conclusion of the Easton study. They have presented a new computational approach for analyzing the impact of missense changes in the DNA-binding domains of the cancer susceptibility protein BRCA2 that uses information from protein sequence, structure, and sequence conservation. They concluded the 2502Cys variant as neutral. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
True Health Diagnostics RCV000131136 SCV000787950 likely benign Hereditary cancer-predisposing syndrome 2018-01-05 no assertion criteria provided clinical testing

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