Submissions for variant NM_000535.7(PMS2):c.241G>T (p.Glu81Ter)

dbSNP: rs730881919

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505890	SCV000601847	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	The PMS2 c.241G>T (p.Glu81*) variant causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in individuals affected with colorectal cancer (PMID: 27589204 (2016)) and CMMRD (PMID: 36647049 (2023)). The frequency of this variant in the general population, 0.000004 (1/250820 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550672	SCV000625615	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu81*) 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). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 27589204). ClinVar contains an entry for this variant (Variation ID: 439243). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000662778	SCV000785586	likely pathogenic	Lynch syndrome 4	2017-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182957	SCV001348569	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with colorectal cancer demonstrating high microsatellite instability (PMID: 27589204). This variant has also been reported in the compound heterozygous state in two unrelated individuals affected with constitutional mismatch repair deficiency (PMID: 36647049). This variant has been identified in 1/250820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center	RCV002305497	SCV002600096	pathogenic	Lynch syndrome 1	2022-11-08	criteria provided, single submitter	clinical testing	This sequence change is nonsense variant introducing Premature Termination Codon. This variant has been detected in patients who developed MSI-H glioblastoma at age 10 or younger, along with another variant, PMS2(NM_000535.7): c.2276-125_2445+1584del (exon 14 deletion, phase unknown).It has also been detected in patients under 20 years of age with PMS2-deficient glioblastoma and colorectal adenocarcinoma in IHC, along with another variant, NC_000007.13: g.5876369_612205del (large deletions including PMS2 gene, located in trans). These two patients are considered constitutional mismatch repair deficiency (CMMRD).
Ambry Genetics	RCV001182957	SCV002732858	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-21	criteria provided, single submitter	clinical testing	The p.E81* pathogenic mutation (also known as c.241G>T), located in coding exon 3 of the PMS2 gene, results from a G to T substitution at nucleotide position 241. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This mutation has been identified in a Japanese colorectal cancer cohort (Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686). 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	RCV003114636	SCV003800805	pathogenic	Hereditary nonpolyposis colon cancer	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.241G>T (p.Glu81X) 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 4e-06 in 250820 control chromosomes, however due to the PMS2 pseudogene these results should be interpreted with caution (gnomAD). c.241G>T has been reported in the literature in an individual affected with colorectal cancer with a MSI-H tumor lacking PMS2 expression by IHC, and in the compound heterozygous state in two unrelated individuals affected with constitutional mismatch repair deficiency (CMMRD) wherein glioblastoma was the initial CMMRD-associated malignancy and the variant was confirmed to be in trans with large PMS2 deletions (Sugano_2016, Onishi_2023). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000662778	SCV004014704	pathogenic	Lynch syndrome 4	2023-04-20	criteria provided, single submitter	clinical testing	The PMS2 c.241G>T (p.Glu81Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in an individual with colorectal cancer, whose tumor cells also lacked PMS2 protein expression (PMID: 27589204). Additionally, the p.Glu81Ter variant was reported in a compound heterozygous state in two individuals with constitutional mismatch repair deficiency and a family history of cancer (PMID: 36647049). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.241G>T (p.Glu81Ter) variant is classified as pathogenic for Lynch syndrome.
Myriad Genetics, Inc.	RCV000662778	SCV004019755	pathogenic	Lynch syndrome 4	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000662778	SCV004203417	pathogenic	Lynch syndrome 4	2021-08-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000505890	SCV005327162	pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Observed in an individual with a personal history consistent with pathogenic variants in this gene (PMID: 27589204); 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; Not observed at significant frequency 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: 36988593, 21376568, 24362816, 29922827, 27589204, 36647049)
Laboratory for Genotyping Development, RIKEN	RCV003159643	SCV002758053	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research