ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.325del (p.Glu109fs) (rs587781716)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129899 SCV000184717 pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 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)
GeneDx RCV000483709 SCV000567847 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing This deletion of one nucleotide in PMS2 is denoted c.325delG at the cDNA level and p.Glu109LysfsX3 (E109KfsX3) at the protein level. The normal sequence, with the base that is deleted in brackets, is CGGGGG[delG]AAGC. The deletion causes a frameshift which changes a Glutamic Acid to a Lysine at codon 109, and creates a premature stop codon at position 3 of the new reading frame. Although this variant has not, to our knowledge, been reported as a germline variant in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Invitae RCV000233229 SCV000285129 pathogenic Hereditary nonpolyposis colon cancer 2019-01-09 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 4 of the PMS2 mRNA (c.325delG), causing a frameshift at codon 109. This creates a premature translational stop signal (p.Glu109Lysfs*3) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.

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