Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.241G>T(p.Glu81Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000139 in 1,441,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E81E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-6003981-C-A is Pathogenic according to our data. Variant chr7-6003981-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Counsyl
Sep 28, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Aug 11, 2021
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Pathogenic, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Apr 03, 2023
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 11, 2023
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. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jan 23, 2023
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. -
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center
Nov 08, 2022
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). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 06, 2023
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. -
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. -