rs1554294508
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000265849.12(PMS2):c.2182_2184delinsG(p.Thr728AlafsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T728T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PMS2
ENST00000265849.12 frameshift
ENST00000265849.12 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.33
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 7-5978687-AGT-C is Pathogenic according to our data. Variant chr7-5978687-AGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.2182_2184delinsG | p.Thr728AlafsTer7 | frameshift_variant | 13/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.2182_2184delinsG | p.Thr728AlafsTer7 | frameshift_variant | 13/15 | 1 | NM_000535.7 | ENSP00000265849 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2020 | The c.2182_2187delACTCTCinsGCTC pathogenic mutation (also known as p.T728Afs*7) , located in coding exon 13 of the PMS2 gene, results from the deletion of 6 nucleotides and insertion of 4 nucleotides at positions 2182 to 2187 causing a translational frameshift with a predicted alternate stop codon. This pathogenic mutation was reported in a female proband diagnosed with colorectal cancer at 51 years of age who met Amsterdam II criteria for Lynch syndrome (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53). 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. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2024 | Variant summary: PMS2 c.2182_2184delinsG (p.Thr728AlafsX7) 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 1594000 control chromosomes. c.2182_2184delinsG has been reported in the literature in individual(s) affected with Lynch Syndrome (e.g. Rossi_2017). The following publication have been ascertained in the context of this evaluation (PMID: 28874130). ClinVar contains an entry for this variant (Variation ID: 231999). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Oncology Research Center, Barretos Cancer Hospital | Aug 01, 2020 | - - |
Lynch syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 22, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, flagged submission | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at