7-5997387-TAGGGGG-TCTTCACACACA
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000265849.12(PMS2):c.736_741delinsTGTGTGTGAAG(p.Pro246CysfsTer3) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P246P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 28)
Consequence
PMS2
ENST00000265849.12 stop_gained, frameshift
ENST00000265849.12 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.33
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 7-5997388-AGGGGG-CTTCACACACA is Pathogenic according to our data. Variant chr7-5997388-AGGGGG-CTTCACACACA is described in ClinVar as [Pathogenic]. Clinvar id is 91366.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.736_741delinsTGTGTGTGAAG | p.Pro246CysfsTer3 | stop_gained, frameshift_variant | 7/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.736_741delinsTGTGTGTGAAG | p.Pro246CysfsTer3 | stop_gained, frameshift_variant | 7/15 | 1 | NM_000535.7 | ENSP00000265849 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
28
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
28
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:24Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2020 | 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 Lynch syndrome (LS) and LS-related cancers as well as in individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome (Clendenning 2008, Senter 2008, Herkert 2011, Alexander 2016, Rosty 2016, Wang 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.736_741del6ins11; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 20205264, 22577899, 18602922, 30702970, 16619239, 24323032, 18178629, 21376568, 20487569, 20093870, 26552419, 25856668, 26895986, 27037742, 22081473, 26845104, 26681312, 27601186, 28418444, 29485237, 28466842, 23733757, 16817031, 21204794, 20682701, 29790872, 30322717, 31992580, 31447099, 33193653, 32719484, 32773772) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 23, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 27, 2022 | The PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs*3) 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 several individuals and families affected with a Lynch syndrome associated cancer and/or polyps (PMIDs: 18602922 (2008), 27435373 (2016), 28466842 (2017), 30702970 (2019)), as well as in an individual affected with CMMRD (PMID: 21376568 (2011)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 13, 2023 | PP4, PP5, PM2_moderate, PM3_strong, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PMS2: PVS1, PS4:Moderate - |
Lynch syndrome 4 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 19, 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 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 14, 2018 | This c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs*3) variant is predicted to result in a premature stop codon and has been reported in multiple individuals with Lynch syndrome-associated tumors (PMID: 16619239, 24323032, 18178629, 21376568). Therefore, c.736_741delinsTGTGTGTGAAG (p.P246Vfs*3) variant in the PMS2 gene is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 16, 2023 | The PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsTer3) change deletes six nucleotides and inserts 11 nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Lynch-syndrome associated cancers, some of which have demonstrated loss of PMS2 by IHC (PMID: 16619239, 24323032, 26681312, 30322717, 33193653). This variant has also been reported in individuals with constitutional mismatch repair deficiency (PMID: 21376568, internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 09, 2014 | - - |
Lynch syndrome Pathogenic:4Other:1
| 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, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as pathogenic and reported on 10/17/2018 by GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 29, 2024 | This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with PMS2-related cancer, and it has been reported as a founder variant in the Icelandic, Swedish, and British populations (PMID: 16619239, 18178629, 28466842). It has also been reported in individuals with a second PMS2 variant and constitutional mismatch repair deficiency (PMID: 21376568, 32773772). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2017 | Variant summary: The PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 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 (e.g. c.823C>T; p.Gln275X, c.861_864delACAG; p.Arg287fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 120338 control chromosomes. The variant of interest has been reported in multiple affected individuals via publications and it was suggested that it might be a founder mutation in Swedish/Scandinavian populations (Clendenning_JMG_2008, van der Klift_Hum Mutat_2016). In addition, IHC performed on tumors showed selective lack of staining of PMS2. Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 23, 2023 | The p.Pro246CysfsX3 variant in PMS2 has been reported in the heterozygous state in more than 15 individuals with Lynch Syndrome-associated cancers (Clendenning 2008 PMID: 18178629, Senter 2008 PMID: 18602922, Ward 2013 PMID: 23733757, Salvador 2019 PMID: 30702970, Djursby 2020 PMID: 33193653, Hartman 2020 PMID: 32782288, Wang 2020 PMID: 31992580, Watson 2021 PMID: 34116445, LMM Internal Data) and in the compound heterozygous state with another loss-of-function PMS2 variant in at least two individuals with constitutional mismatch repair deficiency syndrome (Susswein 2015 PMID: 26681312, Perez-Valencia 2020 PMID: 32773772). The variant segregated with disease in 2 affected individuals from 1 family (Watson 2021 PMID: 34116445). Data from large population studies is insufficient to assess the frequency of this variant. The p.Pro246CysfsX3 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 246 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as Pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (Variation ID 91366). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP criteria applied: PVS1, PS4_Strong, PM3. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 15, 2023 | This variant causes a frameshift and creates a premature translation stop codon in exon 7 of the PMS2 gene. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.736_741del6ins11 in the literature. This variant has been reported as a founder mutation in individuals of Northern European ancestry (PMID: 18178629) and has been detected in individuals affected with Lynch syndrome-associated cancers in Europe, North American and Australia (PMID: 16619239, 18178629, 20682701, 23733757, 24323032, 26681312, 27435373, 28466842, 30702970). This variant also has been observed in individuals with compound heterozygous PMS2 mutations who are affected with constitutional mismatch repair deficiency syndrome (PMID: 21376568, 32773772). 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, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2022 | The c.736_741delCCCCCTinsTGTGTGTGAAG (p.P246Cfs*3) alteration, located in exon 7 (coding exon 7) of the PMS2 gene, consists of a deletion of 6 and insertion of 11 nucleotides causing a translational frameshift at position 736 with a predicted alternate stop codon after 3 amino acids. Of note, this alteration is also known as c.736_741del6ins11 in published literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.002% (5/280588) total alleles studied. The highest observed frequency was 0.004% (5/128304) of European (non-Finnish) alleles. Multiple studies have identified this mutation in association with clinical findings consistent with a diagnosis of Lynch syndrome (Clendenning, 2006; Clendenning, 2008; Talseth-Palmer, 2010; Herkert, 2011; Buchanan, 2014). Subsequent studies have supported this alteration as a founder mutation that arose approximately 1625 years ago, is enriched in individuals with British and Swedish ancestry, and may be associated with reduced penetrance (Clendenning, 2008). A more recent study also found this to be a founder mutation in the Icelandic population (Haraldsdottir, 2017). Based on the available evidence, this alteration is classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 09, 2022 | - - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Pro246CysfsX3 variant was identified in 34 of 2806 proband chromosomes (frequency: 0.012) from individuals or families with endometrial cancer, colorectal cancer, intestinal cancer, cerebral angiosarcoma, (Buchanan 2014, Clendenning 2006, Clendenning 2008, Halvarsson 2006, Herkert 2011, Lagerstedt-Robinson 2007, Senter 2008). The variant was also identified in the following databases: dbSNP (ID: rs267608150) as With Pathogenic allele, ClinVar (classified as pathogenic by InSight, GeneDx, Ambry Genetics, Invitae, OMIM), Clinvitae (as pathogenic), COGR, Insight Colon Cancer Gene Variant Database (32X class5), and the Insight Hereditary Tumors Database (32X class5). The variant was not identifies in Zhejiang Colon Cancer Database or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 5 of 275066 chromosomes at a frequency of 0.00002 (Genome Aggregation Consortium Feb 27, 2017). The c.736_741delinsTGTGTGTGAAG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 246 and leads to a premature stop codon at position 248. 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 colorectal cancer 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. - |
PMS2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2024 | The PMS2 c.736_741delinsTGTGTGTGAAG variant is predicted to result in a frameshift and premature protein termination (p.Pro246Cysfs*3). This variant, also known as c.736_741del6ins11, has been reported in individuals with Lynch syndrome (Clendenning et al. 2006, PubMed ID: 16619239; Clendenning et al. 2008. PubMed ID: 18178629; Salvador MU et al. 2019. PubMed ID: 30702970), endometrial cancer (Buchanan et al. 2014, PubMed ID: 24323032), and in an individual with colon cancer and glioblastoma (Susswein et al. 2015. PubMed ID: 26681312). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91366/). Frameshift variants in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 21, 2021 | Variant summary: PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) 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 1.8e-05 in 279974 control chromosomes. c.736_741delins11 has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Clendenning_2008, vanderKlift_2016) or Endometrial cancer (Buchanan_2014). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Burkitt lymphoma;C0024299:Lymphoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 07, 2017 | This is a frameshift alteration in which coding nucleotides 736 through 741 are deleted and replaced with 11 nucleotides. This is predicted to change a Proline to a Cysteine at amino acid codon 246 and shift the reading frame. Classification criteria: PVS1, PS3, PM2. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2020 | This sequence change deletes 6 nucleotides and inserts 11 nucleotides in exon 7 of the PMS2 mRNA (c.736_741delinsTGTGTGTGAAG), causing a frameshift at codon 246. This creates a premature translational stop signal (p.Pro246Cysfs*3) and is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals and families affected with Lynch syndrome-associated tumors (PMID: 16619239, 24323032, 18178629, 21376568). This variant has been reported as a common cause of Lynch syndrome in individuals with British and Swedish ancestry (PMID: 18178629). It is also known as c.736_741del6ins11 in the literature. ClinVar contains an entry for this variant (Variation ID: 91366). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic. - |
Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Human Genetics, Medical University Innsbruck | May 06, 2020 | This variant, NM_000535.6:c.736_741delinsTGTGTGTGAAG, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.2404C>T. Sample UAB332 in Perez J et al, Genet Med (PMID: 32773772). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at