ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115650 SCV000889605 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing

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