ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.66_67AG[3] (p.Cys24fs) (rs80357914)

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Total submissions: 7
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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) RCV000143834 SCV000299398 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000223371 SCV000273758 pathogenic Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657219 SCV000296302 pathogenic not provided 2019-07-30 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 not found in general population data.
GeneDx RCV000657219 SCV000778945 pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 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.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000779878 SCV000916757 pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) 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 was absent in 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000143834 SCV000115151 pathogenic Breast-ovarian cancer, familial 1 2011-01-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000143834 SCV000144175 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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