rs587778618
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1687C>T(p.Arg563Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R563R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PMS2
NM_000535.7 stop_gained
NM_000535.7 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: 0.466
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 7-5987078-G-A is Pathogenic according to our data. Variant chr7-5987078-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 135067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5987078-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-5987078-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.1687C>T | p.Arg563Ter | stop_gained | 11/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.1687C>T | p.Arg563Ter | stop_gained | 11/15 | 1 | NM_000535.7 | ENSP00000265849 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251330Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135868
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727236
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The p.R563* pathogenic mutation (also known as c.1687C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been detected in an individual diagnosed with a brain tumor at the age of 8 and demonstrated a neurofibromatosis type 1 phenotype; this patient was also identified to carry a PMS2 exon 15 deletion (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Vaughn CP et al. Hum Mutat. 2011 Sep;32:1063-71). This mutation has also been detected in trans with a gross PMS2 deletion involving exons 12 through 14 in a 13-year-old patient diagnosed with rectal cancer and two cafe-au-lait spots, a phenotype consistent with CMMR-D (Vasovcak P et al. DNA Repair (Amst.). 2012 Jul;11:616-23). This alteration was also reported in the homozygous state in a pediatric patient with a personal history of AML and osteosarcoma (Ortiz MV et al. Pediatr Blood Cancer. 2016 08;63:1368-74). Additionally, this alteration has been reported in several individuals with early-onset colorectal cancer whose tumors demonstrated absent PMS2 protein staining on immunohistochemistry (Goodenberger ML et al. Genet Med. 2016 Jan;18:13-9; Wang Q et al. J Med Genet. 2020 07;57:487-499). 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 | curation | Sema4, Sema4 | Mar 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2023 | This variant changes 1 nucleotide in exon 11 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 individuals affected with Lynch syndrome (PMID: 31992580), breast and/or ovarian cancer (31512090, 31650731), and colorectal cancer (PMID: 25856668, 29478780, 31857677). This variant has also been reported in compound heterozygous individuals affected with constitutional mismatch repair deficiency (PMID: 21618646, 22608206). This variant has been identified in 2/251330 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 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 08, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 20, 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 | Baylor Genetics | Feb 13, 2024 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2021 | 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and in a child with personal history suspicious for CMMR-D without a second identifiable PMS2 pathogenic variant (Vaughn 2010, Goodenberger 2016, AlDubayan 2018, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the apparent homozygous state in individuals with personal histories consistent with Constitutional Mismatch Repair Deficiency in the published literature (Vasovcak 2012, Ortiz 2016); 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: 28502729, 29625052, 26689913, 24728327, 25525159, 20205264, 26648449, 27742654, 28281021, 29478780, 30217226, 25856668, 27082517, 22608206, 31992580, 31512090, 31650731, 31857677, 30787465) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 14, 2020 | This nonsense variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with lynch syndrome whose tumors showed loss of PMS protein in Immunohistochemistry assays (PMID: 31992580 (2020)). In addition, this variant has been detected in individuals affected with other cancers including colorectal, breast and/or ovarian, endometrial, kidney and brain cancers (PMIDs: 31857677 (2020), 31650731 (2020), 31512090 (2019), 31336956 (2019), 30103829 (2018), 29478780 (2018), 27376475 (2016), 25194673 (2014), and 20205264 (2010). Also, this variant has been reported in individuals with phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMIDs: 22608206 (2012) and 21618646 (2011)). Based on the available information, this variant is classified as pathogenic. - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Arg563X variant was identified in 5 of 818 proband chromosomes (frequency: 0.006) from individuals or families with Lynch Syndrome, colorectal cancer, endometrial cancer, and biallelic mismatch repair deficiency (Goodenberger 2016, Haraldsdottir 2014, Jansen 2016, Vaughn 2010, Vasovcak 2012). The variant was also identified in the following databases: dbSNP (ID: rs587778618) as "With Pathogenic, Uncertain significance allele", ClinVar (3x, pathogenic), Clinvitae (2x, pathogenic), and Cosmic (3x, confirmed somatic, in carcinomas of the skin and lung). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in one individual with a family history of Lynch Syndrome. The variant was identified in control databases in 2 of 246126 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 15246 chromosomes (freq: 0.0001). The variant was not observed in the other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease 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 | Sep 17, 2024 | The PMS2 c.1687C>T variant is predicted to result in premature protein termination (p.Arg563*). This variant has previously been reported to be causative for colorectal cancer, male breast cancer, constitutional mismatch repair deficiency syndrome and Lynch syndrome (Table S6, AlDubayan et al. 2018. PubMed ID: 29478780; Scarpitta et al. 2019. PubMed ID: 31512090; Vaughn et al. 2010. PubMed ID: 20205264; Vasovcak et al. 2012. PubMed ID: 22608206; Wang et al. 2020. PubMed ID: 31992580; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135067/). Nonsense variants in PMS2 are expected to be pathogenic. 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 | Feb 27, 2023 | Variant summary: PMS2 c.1687C>T (p.Arg563X) 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 251330 control chromosomes (gnomAD). c.1687C>T has been reported in the literature in multiple individuals affected with colorectal cancer, and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (example: Vaughn_2010, Vasovcak_2012, Goodenberger_2015, and Wang_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | The c.1687C>T variant in the PMS2 gene is located on the exon 11 and introduces a premature translation termination codon (p.Arg563*), resulting in an absent or disrupted protein product. This variant has been reported in multiple individuals with Lynch syndrome; colorectal cancer (PMID: 31992580, 31650731, 28514183, 29345684); breast cancer, and endometrial cancer (PMID: 29345684, 31650731, 34994648). This variant has also been reported in compound heterozygosity in an individual with constitutional mismatch repair deficiency syndrome (PMID: 22608206). Loss-of-function variants in PMS2 gene are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 135067). The variant is rare in general population database according to gnomAD (2/251330 chromosomes). Therefore, the c.1687C>T (p.Arg563*) variant in PMS2 gene has been classified as pathogenic. - |
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Arg563*) 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 (rs587778618, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colorectal cancer, breast cancer and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 20205264, 22608206, 25856668). ClinVar contains an entry for this variant (Variation ID: 135067). For these reasons, this variant has been classified as Pathogenic. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;N;N
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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