Submissions for variant NM_000535.7(PMS2):c.703C>T (p.Gln235Ter)

dbSNP: rs63750261

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076882	SCV000108376	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000132294	SCV000187379	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-26	criteria provided, single submitter	clinical testing	The p.Q235* pathogenic mutation (also known as c.703C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 703. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation was reported in a Swiss early-onset colorectal cancer patient whose tumor showed loss of expression of PMS2 on IHC and whose family history met Amsterdam criteria (Truninger K et al. Gastroenterology, 2005 May;128:1160-71). This variant has also been reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx	RCV001762199	SCV002009014	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 32719484, 15887099)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778704	SCV002015158	pathogenic	Hereditary nonpolyposis colon cancer	2021-10-03	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.703C>T (p.Gln235X) 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. In addition, as the variant alters a conserved nucleotide located in the putative exonic splice region close to the canonical splice donor site, several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. Either of these variant effects, namely truncation or splicing impact, will result in a loss of PMS2 function. The variant was absent in 251490 control chromosomes. c.703C>T has been reported in the literature in individuals affected with colorectal cancer and has also been reported as a pathogenic finding in at-least one individual undergoing population screening in the Healthy Nevada project (example, Truninger_2005, Espenschied_2017, Grzymski_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, although an expert panel (InSIGHT) and a clinical diagnostic laboratory have submitted clinical-significance assessments as pathogenic before 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001854344	SCV002157753	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln235*) in the PMS2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15887099, 28514183). ClinVar contains an entry for this variant (Variation ID: 91363). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288576	SCV002580581	pathogenic	Lynch syndrome 4	2022-06-03	criteria provided, single submitter	clinical testing