ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4754_4755del (p.Pro1585fs) (rs80357837)

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Total submissions: 8
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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) RCV000112394 SCV000300159 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Michigan Medical Genetics Laboratories,University of Michigan RCV000112394 SCV000267715 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000219878 SCV000273783 pathogenic Hereditary cancer-predisposing syndrome 2015-01-29 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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112394 SCV000326041 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000483332 SCV000566842 pathogenic not provided 2015-06-05 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in BRCA1 is denoted c.4754_4755delCA at the cDNA level and p.Pro1585ArgfsX36 (P1585RfsX36) at the protein level. The normal sequence, with the bases that are deleted in braces, is GCCC[CA]GAGT. The deletion causes a frameshift, which changes a Proline to an Arginine at codon 1585, and creates a premature stop codon at position 36 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.4754_4755delCA, previously reported as BRCA1 4873delCA, has been observed in at least one individual with Hereditary Breast and Ovarian Cancer (Caligo 1996). we consider this variant to be pathogenic.
Color RCV000219878 SCV000683211 pathogenic Hereditary cancer-predisposing syndrome 2016-03-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000607763 SCV000731762 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-20 criteria provided, single submitter clinical testing The p.Pro1585fs variant in BRCA1 has been reported in at least 5 individuals wit h breast cancer (Ghili 2017, Caligo 1996, Breast Cancer Information Core (BIC) d atabase) and was absent from large population studies, though the ability of the se studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1585 and leads to a premature termination codon 36 amino acids down stream. This alteration is then predicted to lead to a truncated or absent prote in. Heterozygous loss of function of the BRCA1 gene is an established disease me chanism in hereditary breast and ovarian cancer (HBOC). In addition, this varian t was classified as pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA ex pert panel (ClinVar SCV000300159.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individual s.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112394 SCV000145174 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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