ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5569del (p.Glu1857fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004018131 SCV004848445 likely pathogenic Hereditary breast ovarian cancer syndrome 2020-08-10 criteria provided, single submitter clinical testing The p.Glu1857LysfsX6 variant in BRCA2 has been reported as a germline variant in 1 individual with an exocrine pancreatic neoplasm (Lowery 2018 PMID:29506128) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1857 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics RCV004372002 SCV005028189 pathogenic Hereditary cancer-predisposing syndrome 2023-02-06 criteria provided, single submitter clinical testing The c.5569delG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 5569, causing a translational frameshift with a predicted alternate stop codon (p.E1857Kfs*6). This alteration was identified in an individual diagnosed with pancreatic cancer (Lowery MA et al. J Natl Cancer Inst, 2018 Oct;110:1067-1074). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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