ClinVar Miner

Submissions for variant NM_007300.4(BRCA1):c.5566C>T (p.Arg1856Ter) (rs41293465)

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Total submissions: 24
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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) RCV000077627 SCV000282345 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000203652 SCV000077033 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the BRCA1 mRNA at codon 1835 (p.Arg1835*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 28 amino acids of the BRCA1 protein, including a portion of the C-terminal BRCT-C functional domain (PMID: 22843421, 11157798). This variant is not present in population databases (rs41293465, ExAC no frequency). This variant has been reported in many individuals and families affected with breast, ovarian, and bladder cancer (PMID: 27553291, 8554067, 10486320, 11802209, 16683254, 19949876, 23704984). This variant is also known as 5622C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55601). Experimental studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it disrupts chromatin structure by increasing chromatin unfolding, a marker of impaired BRCA1 function (PMID: 11739404). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131862 SCV000186917 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000049020 SCV000210227 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5503C>T at the cDNA level and p.Arg1835Ter (R1835X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay has been shown to not occur (Perrin-Vidoz 2002), it is significant since the last 29 amino acids are no longer translated, disrupting the second BRCT domain and a region known to interact with many proteins (Paul 2014, UniProt). BRCA1 Arg1835Ter, previously reported as BRCA1 5622C>T using alternate nomenclature, has been reported in association with hereditary breast and/or ovarian cancer (Serova 1996, Meindl 2002, Rashid 2006, van der Hout 2006, Borg 2010, Cunningham 2014, Kwong 2016). We consider this variant to be pathogenic.
Counsyl RCV000077627 SCV000220880 likely pathogenic Breast-ovarian cancer, familial 1 2014-11-14 criteria provided, single submitter literature only
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240766 SCV000265868 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000049020 SCV000296284 pathogenic not provided 2015-07-13 criteria provided, single submitter clinical testing
GeneKor MSA RCV000238956 SCV000296784 pathogenic Familial cancer of breast 2017-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735447 SCV000324836 pathogenic Breast and/or ovarian cancer 2015-09-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077627 SCV000326344 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000131862 SCV000537638 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077627 SCV000564353 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000203652 SCV000591636 pathogenic Hereditary breast and ovarian cancer syndrome 2012-09-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000203652 SCV000699267 pathogenic Hereditary breast and ovarian cancer syndrome 2014-06-18 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077627 SCV000743370 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077627 SCV000744581 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000049020 SCV000806977 pathogenic not provided 2017-11-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077627 SCV000109430 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077627 SCV000145551 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000077627 SCV000238467 pathogenic Breast-ovarian cancer, familial 1 2015-03-20 no assertion criteria provided research The heterozygous variant in the BRCA1 gene (c.5503C>T; p.Arg1835*)is considered pathogenic. This change results in a premature stop codon interrupting an important functional domain BRCT2 (PMID: 11739404) and premature truncation results in impaired function. This variant has been previously published in 2 individuals of Punjabi ethnicity and part of a cohort of unrelated Pakistani individuals with breast and ovarian cancer (PMID: 16998791), though the paper has no additional information on the phenotype of the affected individuals. This variant has also been seen in multiple affected individuals by other clinical labs (SCV000109430, SCV000145551, SCV000186917, SCV000210227, SCV000077033).
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000203652 SCV000587514 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077627 SCV000733584 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735447 SCV000863583 pathogenic Breast and/or ovarian cancer 2012-07-14 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785213 SCV000923781 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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