ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5182del (p.Met1728fs) (rs34570933)

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Total submissions: 4
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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) RCV000661377 SCV000783650 pathogenic Breast-ovarian cancer, familial 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000657204 SCV000778930 pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.5182delA at the cDNA level and p.Met1728CysfsX2 (M1728CfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAA[delA]TGCT. The deletion causes a frameshift which changes a Methionine to a Cysteine at codon 1728, and creates a premature stop codon at position 2 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.5182delA, also published as BRCA1 5301delA, has been observed in an individual with ovarian cancer and a family history of breast and/or ovarian cancer (Walsh 2011). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000779873 SCV000916747 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-17 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5182delA (p.Met1728CysfsX2) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.5239C>T, p.Gln1747X; c.5251C>T, p.Arg1751X; c.5266dupC, p.Gln1756fsX74). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 245904 control chromosomes (gnomAD). This variant was reported in one patient with serous ovarian cancer (Walsh_2011). This variant is located in a mutation hotspot in close proximity to other known pathogenic variants in exon 19 such as c.5174_5177delAAAG (p.Arg1726LysfsX3), c.5177_5180delGAAA (p.Arg1726LysfsX3), and c.5179A>T (p.Lys1727X). Taken together, this variant is classified as pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577450 SCV000679305 not provided Familial cancer of breast no assertion provided literature only

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