ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1112_1113delinsTTTA (p.Asn371fs) (rs587779326)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076795 SCV000108277 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000115650 SCV000149559 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted PMS2 c.1112_1113delATinsTTTA at the cDNA level and p.Asn371IlefsX2 (N371IfsX2) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is CTAA[delAT][insTTTA]GTCA. The variant causes a frameshift which changes an Asparagine to an Isoleucine at codon 371, 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.1112_1113delATinsTTTA, also reported as c.1112_1113delinsTTTA, has been reported in a family with Lynch syndrome and in an individual with breast cancer, and was shown functionally to result in a lack of mRNA expression (Suerink 2015, Susswein 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115650 SCV000889605 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing
Invitae RCV000813059 SCV000953396 pathogenic Hereditary nonpolyposis colon cancer 2018-07-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn371Ilefs*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 in an individual with breast cancer (PMID: 26681312 ), as well as in a family affected with Lynch syndrome (PMID: 26110232). ClinVar contains an entry for this variant (Variation ID: 91290). Experimental studies have shown that this change results in loss of RNA expression (PMID: 26110232). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001017357 SCV001178430 pathogenic Hereditary cancer-predisposing syndrome 2019-09-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV001017357 SCV001351215 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193255 SCV001361983 pathogenic Hereditary nonpolyposis colon cancer 2019-10-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1112_1113delinsTTTA (p.Asn371IlefsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251318 control chromosomes (gnomAD). c.1112_1113delinsTTTA has been reported in the literature in a family affected with Lynch Syndrome (Suerink_2015) and in at least one individual with a history of breast cancer (Susswein_2016, Roberts_2018). These data indicate that the variant is likely to be associated with disease. In functional studies, no mRNA expression was seen from the mutated allele (Suerink_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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