rs587779343
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.697C>T(p.Gln233*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000682 in 1,613,882 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
PMS2
NM_000535.7 stop_gained
NM_000535.7 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.36
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 7-5999116-G-A is Pathogenic according to our data. Variant chr7-5999116-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91362.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5999116-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152046Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251492Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461836Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727230
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74254
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 24, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 26, 2024 | Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19132747, 20186688, 27694994, 26681312, 28874130, 27435373, 25512458, 30787465, 31332305, 33087929, 29922827, 35534704, 26110232, 29345684, Chelal2022[article]) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Lynch syndrome 4 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 06, 2019 | ACMG classification criteria: PVS1, PS4, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 19, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 10, 2021 | _x000D_ Criteria applied: PVS1, PS4 - |
Lynch syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.697C>T;p.(Gln233*) variant creates a premature translational stop signal in the PMS2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91362; PMID: 19132747; PMID: 20186688; PMID: 27435373) - PS4. The variant is present at low allele frequencies population databases (rs587779343 – gnomAD 0.0001061%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. The variant was identified in an individual with a highly specific phenotype for the condition (PMID: 19132747, 27435373) - PP4. In summary, the currently available evidence indicates that the variant is 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Gln233X variant in PMS2 has been previously reported in >15 individuals with PMS2-associated cancers (Rossi 2017, van der Klift 2016, Susswein 2016, Suerink 2016, ten Broeke 2015, Niessen 2009) and has been detected in 3/129188 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91362). This nonsense variant leads to a premature termination codon at position 233, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 04, 2021 | This variant changes 1 nucleotide in exon 6 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 16472587, 19132747, 25512458, 26110232, 27435373, 28874130) and breast/ovarian cancer (PMID: 27153395, 29345684, 33471991; DOI: 10.1101/2021.04.15.21255554). This variant has been identified in 3/282860 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The p.Q233* pathogenic mutation (also known as c.697C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 697. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This alteration was first reported in an individual with a uterine sarcoma diagnosed at 52 years and colorectal carcinoma (exhibiting microsatellite instability) diagnosed at 62 and 63 years (Niessen RC et al. Genes Chromosomes Cancer 2009 Apr;48:322-9). It has since been reported in multiple families with Lynch syndrome associated cancers (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33:319-25; van der Klift HM et al. Hum. Mutat. 2016 11;37(11):1162-1179; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). Furthermore, this alteration has been shown to result in nonsense mediated mRNA decay by RT-PCR (van der Klift HM et al. Hum. Mutat. 2010 May;31:578-87). 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. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2025 | Variant summary: PMS2 c.697C>T (p.Gln233X) 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 allele was found at a frequency of 8e-06 in 251542 control chromosomes. c.697C>T has been reported in the literature in individuals affected with clinical features of PMS2-related conditions (example, Niessen_2009, van der Klift_2016, van der Klift_2010, Susswein_2016). The following publications have been ascertained in the context of this evaluation (PMID: 19132747, 20186688, 26681312, 27435373). ClinVar contains an entry for this variant (Variation ID: 91362). 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 | Nov 18, 2024 | This sequence change creates a premature translational stop signal (p.Gln233*) 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 (rs587779343, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and suspected Lynch syndrome (PMID: 19132747, 20186688, 25512458, 26110232, 27435373). ClinVar contains an entry for this variant (Variation ID: 91362). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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