ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2361_2364del (p.Phe788fs) (rs267608160)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572699 SCV000674247 pathogenic Hereditary cancer-predisposing syndrome 2016-11-11 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 RCV000657184 SCV000778906 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing This deletion of four nucleotides in PMS2 is denoted c.2361_2364delCTTC at the cDNA level and p.Phe788CysfsX2 (F788CfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGAT[delCTTC]ATGC. The deletion causes a frameshift which changes a Phenylalanine to a Cysteine at codon 788, 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.2361_2364delCTTC was identified in trans with another PMS2 frameshift variant in a patient with constitutional mismatch repair deficiency syndrome (De Rosa 2000). We consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076853 SCV000108345 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000629975 SCV000750931 pathogenic Hereditary nonpolyposis colon cancer 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe788Cysfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Turcot's syndrome (PMID: 10763829). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 91338). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009817 SCV000030038 pathogenic Turcot syndrome 2000-03-23 no assertion criteria provided literature only

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