rs587781626
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1PP5_Very_Strong
The NM_000535.7(PMS2):c.2500_2501delATinsG(p.Met834GlyfsTer17) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.
Frequency
Consequence
NM_000535.7 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant results in the replacement of two nucleotides in exon 15 of the PMS2 gene with one new nucleotide, creating a frameshift at codon 834 in a predicated truncated protein. While this variant is not expected to trigger nonsense-mediated decay, a truncated C-terminal polypeptide (lacking a.a. 826-850) has previously been shown to lack binding to MLH1 (PMID: 10037723) and single missense mutations in codons 843, 845 and 847 have been shown to disrupt DNA mismatch repair in vitro (PMID: 18619468). This variant is expected to result in a non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancer or suspected of Lynch syndrome (PMID: 23012243, 25856668, 28514183, 30322717; ClinVar SCV000184533.8). Moreover, further C-terminal truncation at codon 836 and a frameshift at codon 841 have been observed in an individual suspected of Lynch syndrome (PMID: 28514183) and individuals affected with biallelic constitutional mismatch repair deficiency syndrome (PMID: 26116798, 30764633), respectively. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The c.2500_2501delATinsG pathogenic mutation, located in coding exon 15 of the PMS2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.M834Gfs*17). This alteration occurs at the 3' terminus of thePMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including multiple probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry (Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Carcinoma of colon Pathogenic:1
The PMS2 p.Met834Glyfs*17 variant was identified in 3 of 69960 proband chromosomes (frequency: 0.00004) from individuals or families with Lynch Syndrome (Espenschied 2017). The variant was also identified in ClinVar (classified as pathogenic by Ambry Genetics, Invitae), Clinvitae (classified as pathogenic by ClinVar), Insight Hereditary Tumors Database, databases. The variant was not identified in dbSNP, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.2500_2501delinsG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 834 and leads to a premature stop codon at position 850. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch Syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.2500_2501delinsG (p.Met834GlyfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however, nonsense mediated decay is not expected to occur. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 145224 control chromosomes. c.2500_2501delinsG has been reported in the literature in individuals affected with Lynch Syndrome and associated cancers (e.g. Carter_2018, Espenschied_2017, Goodenberger_2015, LaDuca_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25856668, 28152038, 28514183, 30322717). ClinVar contains an entry for this variant (Variation ID: 141280). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
The PMS2 c.2500_2501delinsG (p.Met834Glyfs*17) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in individuals affected with Lynch syndrome-related cancers (PMID: 25856668 (2015), 23012243 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Met834Glyfs*17) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome (CMMR-D) and/or clinical features of Lynch syndrome (PMID: 23012243, 25856668, 28514183, 30322717; Scientific presentation). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 141280). This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). While functional studies have not been performed to directly test the effect of this variant on PMS2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -
Lynch syndrome 4 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at