rs63750246
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.862_863delCA(p.Gln288fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PMS2
NM_000535.7 frameshift
NM_000535.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.57
Genes affected
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]
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ACMG classification
Classification made for transcript
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 7-5995573-CTG-C is Pathogenic according to our data. Variant chr7-5995573-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 91376.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5995573-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.862_863delCA | p.Gln288fs | frameshift_variant | 8/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.862_863delCA | p.Gln288fs | frameshift_variant | 8/15 | 1 | NM_000535.7 | ENSP00000265849.7 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461744Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727194
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome 4 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 13, 2016 | - - |
Lynch syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant deletes 2 nucleotides in exon 8 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer, whose tumor demonstrated microsatellite instability and loss of PMS2 protein via immunohistochemistry analysis (PMID: 16619239). This variant has not been identified 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. - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 11, 2024 | The PMS2 c.862_863del (p.Gln288Valfs*10) 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 with suspected Lynch syndrome (PMID: 16619239 (2006)), ovarian cancer (PMID: 28888541 (2017)), and colorectal cancer (PMID: 18602922 (2008)). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2023 | Frameshift 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 individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 16619239, 18602922, 28514183); 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: 30787465, 28514183, 28888541, 27435373, 18602922, 16619239, 36644715) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2023 | The c.862_863delCA pathogenic mutation, located in coding exon 8 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 862 to 863, causing a translational frameshift with a predicted alternate stop codon (p.Q288Vfs*10). This alteration has been reported in an individual with colon cancer at age 54 with absent PMS2 IHC expression (Clendenning M, Hum. Mutat. 2006 May; 27(5):490-5.) In addition, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | Oct 18, 2023 | This variant deletes 2 nucleotides in exon 8 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer, whose tumor demonstrated microsatellite instability and loss of PMS2 protein via immunohistochemistry analysis (PMID: 16619239). This variant has not been identified 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. - |
PMS2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2024 | The PMS2 c.862_863delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln288Valfs*10). This variant was reported in an individual with Lynch syndrome (Clendenning et al 2006. PubMed ID: 16619239). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in PMS2 are expected to be pathogenic. This variant is listed in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/91376/). This variant is interpreted 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 | Aug 07, 2020 | Variant summary: PMS2 c.862_863delCA (p.Gln288ValfsX10) 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. The variant was absent in 251446 control chromosomes (gnomAD). c.862_863delCA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Clendenning_2006, Espenschied_2017, Senter_2008). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Gln288Valfs*10) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 16619239, 18602922). ClinVar contains an entry for this variant (Variation ID: 91376). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at