ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter) (rs63751466)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076858 SCV000108349 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000129304 SCV000184066 pathogenic Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000409056 SCV000488733 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000413126 SCV000490734 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.2404C>T at the cDNA level and p.Arg802Ter (R802X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been observed in the heterozygous state in individuals with Lynch syndrome and in the homozygous state in several individuals with constitutional mismatch repair deficiency syndrome (De Vos 2004, De Vos 2006, Senter 2008, Vaughn 2010, Ten Broeke 2015, Rosty 2016, Andrianova 2017). We therefore consider PMS2 Arg802Ter to be pathogenic.
Invitae RCV000524467 SCV000551948 pathogenic Hereditary nonpolyposis colon cancer 2020-01-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal near the end of the penultimate exon of the PMS2 mRNA (p.Arg802*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 61 amino acids of the PMS2 protein. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in the literature in several individuals and families affected with Lynch syndrome-related cancers (PMID: 18602922, 26110232, 25512458, 26895986). It has also been observed in the homozygous state in individuals affected with childhood-onset hematological malignancies and brain tumors (PMID: 16507833, 15077197, 28805995). ClinVar contains an entry for this variant (Variation ID: 9237). Different truncations downstream of this variant (p.Met834Glyfs*17 and a deletion of exon 15) have been determined to be pathogenic (PMID: 23012243, 10037723, 2440087, 21618646). This suggests that deletion of this region of the PMS2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009818 SCV000030039 pathogenic Turcot syndrome 2006-03-01 no assertion criteria provided literature only

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