ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.746_753del (p.Asp249fs) (rs587782710)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132182 SCV000187261 pathogenic Hereditary cancer-predisposing syndrome 2014-03-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000222778 SCV000275106 pathogenic Tumor susceptibility linked to germline BAP1 mutations 2015-04-10 criteria provided, single submitter clinical testing
Invitae RCV000227297 SCV000285153 pathogenic Hereditary nonpolyposis colon cancer 2019-10-07 criteria provided, single submitter clinical testing This sequence change deletes 8 nucleotides from exon 7 of the PMS2 mRNA (c.746_753delACTCCGTG), causing a frameshift at codon 249. This creates a premature translational stop signal (p.Asp249Valfs*2) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with colorectal cancer and suspected Lynch syndrome (PMID: 20487569, 25980754, 27435373, 27064304). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657186 SCV000778908 pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing This deletion of eight nucleotides in PMS2 is denoted c.746_753delACTCCGTG at the cDNA level and p.Asp249ValfsX2 (D249VfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGTG[delACTCCGTG]TGTG. The deletion causes a frameshift, which changes an Aspartic Acid to a Valine at codon 249, 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. PMS2 c.746_753delACTCCGTG has been reported in individuals with colon cancer (Talseth-Palmer 2010, Goodenberger 2016). We consider this variant to be pathogenic.

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