ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6322C>T (p.Arg2108Cys) (rs55794205)

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Total submissions: 25
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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) RCV000113572 SCV001161523 benign Breast-ovarian cancer, familial 2 2019-06-18 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 = 0.000248
Invitae RCV000044911 SCV000072924 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129227 SCV000183981 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.
GeneDx RCV000034453 SCV000210627 likely benign not provided 2020-09-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21671020, 22713736, 24728327, 28477318, 28324225, 18284688, 30254663, 17972177, 25782689, 24323938, 24489791, 22703879, 21520273, 23469205, 23328489, 18627636, 20104584, 25777348, 26183948, 22874498, 15172753, 24504028, 28222693, 27376475, 29061375, 28664449, 28392550, 28651617, 29302806, 21218378, 27882536, 30093976, 32072338)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735585 SCV000219376 benign Breast and/or ovarian cancer 2016-03-09 criteria provided, single submitter clinical testing
Counsyl RCV000113572 SCV000220889 likely benign Breast-ovarian cancer, familial 2 2014-11-16 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000113572 SCV000267793 benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113572 SCV000383736 likely benign Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000384925 SCV000383737 likely benign Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044911 SCV000494352 benign Hereditary breast and ovarian cancer syndrome 2015-04-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129227 SCV000683773 likely benign Hereditary cancer-predisposing syndrome 2015-04-22 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113572 SCV000743318 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000113572 SCV000744486 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120335 SCV000805739 benign not specified 2017-08-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034453 SCV001248280 likely benign not provided 2019-07-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642546 SCV001854878 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034453 SCV000043220 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000120335 SCV000084487 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000113572 SCV000146824 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000120335 SCV000587835 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120335 SCV000592042 benign not specified no assertion criteria provided clinical testing The p.Arg2108Cys variant has been reported in the literature in 13/16,018 proband chromosomes from individuals with hereditary breast and/or ovarian cancer, although no control chromosomes were tested to establish the variant's frequency in the general population (Balia 2011, Capanu 2011, Purnomosari 2007, Borg 2010, Thirthagiri 2008, Jalkh 2012). There is conflicting evidence in the literature regarding its pathogenicity. It has been identified in the BIC database (x22) with unknown clinical importance, and in the LOVD and UMD databases (x5). The variant was identified in an individual who also had a pathogenic BRCA2 mutation c.5835_5842dup (p.Cys1948TyrfsX18) (UMD), and this finding increases the likelihood that the p.Arg2108Cys variant does not have clinical significance (notably compound heterozygous variants in the BRCA2 gene are expected to cause fanconi anemia but the phenotype was not provided in this case). In a functional assay that evaluated the effect of the transient overexpression of the p.Arg2108Cys variant on spontaneous homologous recombination (HR) in a HeLa cell line, the variant increased HR as much as a pathogenic variant G2748D, which led the authors to classify it as possibly pathogenic (Balia 2011), but the relevance of these findings in a cell model to the in-vivo organism remains questionable. It is listed in dbSNP database (ID#:rs55794205) as coming from a "clinical source" with a global minor allele frequency (MAF) of 0.002/5. Another variant at this position (p.Arg2108His) has been observed 126 times in the BIC database with unknown clinical significance, but this relatively high frequency may suggest that the variant is a common benign variant. In addition, this p.Arg2108 residue is not conserved in mammals and the variant amino acid Cys (Cysteine) is present in monkey, mouse, rat, cat and dog, increasing the likelihood that a change to this amino acid does not have functional significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not very predictive of pathogenicity. Myriad genetics reports this variant as a polymorphism (personal communication). In summary, based on the above information. This variant meets our lab's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000034453 SCV000778696 likely benign not provided 2017-04-21 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735585 SCV000863723 uncertain significance Breast and/or ovarian cancer 2013-03-15 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000034453 SCV001905985 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000034453 SCV001956829 likely benign not provided no assertion criteria provided clinical testing

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