Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.823C>T(p.Gln275Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,770 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q275Q) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.
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]
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-5995614-G-A is Pathogenic according to our data. Variant chr7-5995614-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5995614-G-A is described in Lovd as [Pathogenic].
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Aug 05, 2022
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; This variant is associated with the following publications: (PMID: 24689082, 26681312, 28514183, 26110232, 23012243, 25512458, 31992580, 31447099, 30787465, 33087929, 22848017) -
Pathogenic, no assertion criteria provided
clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
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Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Dec 18, 2022
This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251410 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 31992580 (2020), 25512458 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Aug 03, 2022
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Lynch syndrome 4 Pathogenic:5
Pathogenic, criteria provided, single submitter
clinical testing
MGZ Medical Genetics Center
May 02, 2022
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Oct 22, 2023
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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
research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Apr 26, 2021
ACMG codes:PVS1; PS4M; PM2; PP5 -
Pathogenic, criteria provided, single submitter
clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Nov 26, 2017
This c.823C>T (p.Gln275*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with cancer (PMID: 22848017, 25512458, 24689082, 26681312). The c.823C>T (p.Gln275*) variant in the PMS2 gene is classified as pathogenic. -
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Oct 14, 2019
The p.Gln275X variant in PMS2 has been reported in at least 4 heterozygous individuals with PMS2-associated cancers and in 1 compound heterozygous individual with constitutive mismatch repair deficiency (Espenschied 2017, Susswein 2016, Suerink 2016, Hansen 2014, Vaughn 2013, Yeung 2013). This variant has been identified in 2/34590 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (pathogenic by several clinical labs (ClinVar ID 127796). This nonsense variant leads to a premature termination codon at position 275, 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_Supporting, PM3. -
Pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 13, 2023
The c.823C>T (p.Gln275*) variant in the PMS2 gene is located on the exon 8 and introduces a premature translation termination codon (p.Gln275*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer or constitutional mismatch repair-deficiency syndrome (PMID: 28514183, 24689082, 27435373, 26110232, 23012243, 22848017). Loss-of-function variants in PMS2 are known to be pathogenic and variants located downstream to this position in this exon have been reported as pathogenic (PMID: 28514183, 25512458, 35223509, p.Gln288fs, ClinVar ID: 91376). The variant is reported in ClinVar (ID: 127796). The variant is rare in the general population according to gnomAD (2/251410). Therefore, the c.823C>T (p.Gln275*) variant of PMS2 has been classified as pathogenic. -
The p.Q275* pathogenic mutation (also known as c.823C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in two Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome families in the Netherlands (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33(4):319-25); in a child diagnosed with constitutional mismatch repair deficiency (CMMR-D) who also had a second PMS2 mutation (Yeung JT et al. Pediatr Blood Cancer. 2013 Jan;60(1):137-9); and in a patient with endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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
Sep 05, 2023
This variant changes 1 nucleotide in exon 8 of the PMS2 gene, creating a 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 constitutional mismatch mismatch repair deficiency who also carried another pathogenic PMS2 variant in trans (PMID: 22848017), as well as in multiple individuals affected with Lynch syndrome (PMID: 25512458, 27435373, 31992580). This variant has been identified in 2/251410 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. -
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
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Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 28, 2020
Variant summary: PMS2 c.823C>T (p.Gln275X) 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 8e-06 in 251410 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Yeung_2013, Hansen_2014, ten Broeke_2015, van der Klift_2016, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Gln275*) 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 (rs587780062, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, and constitutional mismatch repair deficiency (PMID: 23012243, 24689082, 26110232). ClinVar contains an entry for this variant (Variation ID: 127796). For these reasons, this variant has been classified as Pathogenic. -