ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2433del (p.Lys812fs) (rs80357524)

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Total submissions: 16
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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) RCV000031050 SCV000299767 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000047838 SCV000075851 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys812Argfs*3) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported individuals affected with breast and/or ovarian cancer (PMID: 16030099, 22798144, 23233716). This variant is also known as 2552delC in the literature. ClinVar contains an entry for this variant (Variation ID: 37469). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000129993 SCV000184817 pathogenic Hereditary cancer-predisposing syndrome 2018-03-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000236325 SCV000292512 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.2433delC at the cDNA level and p.Lys812ArgfsX3 (K812RfsX3) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]AAGG. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 812, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2433delC, previously reported as BRCA1 2552delC using alternate nomenclature, has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer and is a recurrent variant in Hispanic and Korean populations (Ahn 2007, Hall 2009, Weitzel 2013, Choi 2015, Torres-Mejia 2015). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236325 SCV000296330 pathogenic not provided 2019-05-31 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031050 SCV000325356 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031050 SCV000488851 pathogenic Breast-ovarian cancer, familial 1 2016-07-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047838 SCV000591388 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000236325 SCV000806916 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing
Color RCV000129993 SCV000911074 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047838 SCV000916767 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2433delC (p.Lys812ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 245706 control chromosomes (gnomAD). The variant, c.2433delC, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Han_2006, Weitzel_2005, Lim_2009, Vogel_2007, John_2007, Mgbemena_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000031050 SCV000996164 pathogenic Breast-ovarian cancer, familial 1 2018-06-29 criteria provided, single submitter clinical testing This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer (PMID: 25863477, 16455195, 25371446, 23233716). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/245,372) and thus is presumed to be rare. Based on the available evidence, the c.2433delC (p.Lys812ArgfsTer3) variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031050 SCV000053644 pathogenic Breast-ovarian cancer, familial 1 2014-01-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031050 SCV000144435 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000031050 SCV000189892 pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047838 SCV000587217 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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