Submissions for variant NM_000535.7(PMS2):c.802dup (p.Tyr268fs)

dbSNP: rs267608149

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076888	SCV000108384	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000815163	SCV000955610	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91369). This variant is also known as c.802_803insT. This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 18602922). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr268Leufs*31) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076888	SCV000966983	pathogenic	Lynch syndrome	2017-12-14	criteria provided, single submitter	clinical testing	The p.Tyr268fs variant in PMS2 has been reported in at least 1 individual with P MS2-associated cancer and absence of PMS2 by IHC in the tumor (Senter 2008, Rost y 2016). It was also identified in 1/30264 South Asian and 1/110626 European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org). This variant is predicted to cause a frameshift, which alters the protei n?s amino acid sequence beginning at position 268 and leads to a premature termi nation codon 31 amino acids downstream. This alteration is then predicted to lea d to a truncated or absent protein. Heterozygous loss of function of the PMS2 ge ne is an established disease mechanism in Lynch syndrome. In addition, this vari ant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved In SIGHT expert panel (ClinVar SCV000108384.2). In summary, this variant meets crit eria to be classified as pathogenic for Lynch syndrome in an autosomal dominant based upon predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PP 4.
Ambry Genetics	RCV002415571	SCV002681153	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-08	criteria provided, single submitter	clinical testing	The c.802dupT pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a duplication of T at nucleotide position 802, causing a translational frameshift with a predicted alternate stop codon (p.Y268Lfs*31). This mutation has been reported in at least one individual with a colorectal tumor demonstrating isolated loss of PMS2 by IHC (Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Rosty C et al. BMJ Open 2016 Feb;6:e010293). Of note, this alteration is also designated as c.802_803insT in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469006	SCV002766074	pathogenic	Hereditary nonpolyposis colon cancer	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.802dupT (p.Tyr268LeufsX31) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248746 control chromosomes. c.802dupT has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer. These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV003137614	SCV003818334	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452996	SCV004188633	pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.