rs587782704
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.2117delA(p.Lys706fs) variant causes a 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PMS2
NM_000535.7 frameshift
NM_000535.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
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 7-5982880-CT-C is Pathogenic according to our data. Variant chr7-5982880-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 142765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5982880-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000825 AC: 12AN: 1454606Hom.: 0 Cov.: 30 AF XY: 0.00000968 AC XY: 7AN XY: 723348
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
12
AN:
1454606
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Cov.:
30
AF XY:
AC XY:
7
AN XY:
723348
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome 4 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 19, 2017 | The c.2117delA (p.Lys706Serfs*19) variant has been in a 53 y/o female with colorectal cancer in the transverse colon [PMID 5856668], an also detected in a family with Lynch syndrome [PMID 26110232]. This variant was also recently detected at the homozygous state in 2 young siblings with recurrent gliobalstoma multiforme and NF1 features [PMID 27001570]. Treatment with the anti-programmed death-1 inhibitor nivolumab resulted in clinically significant responses and a profound radiologic response. This variant was not observed in the ExAC population database nor in our patient cohort. This 1 bp deletion is located in exon 12, and leads to a frameshift and a premature stop codon. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. Pathogenic variant in the PMS2 gene are considered medically actionable [ACMG59, PMID 27854360] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Nov 06, 2019 | This variant leads to a translational frameshift and the introduction of a premature termination codon 19 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PMS2 is a well-established mechanism of disease for Lynch syndrome. This variant has been reported in the literature in an individual with colon cancer (Leiter 1965) and a family with Lynch syndrome (Suerink 2016). It has also been reported in individuals with constitutional mismatch repair deficiency syndrome (Bouffet 2016, Adam 2016). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1; PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 21, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 30, 2020 | DNA sequence analysis of the PMS2 gene demonstrated a 1 base pair deletion in exon 12, c.2117del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 18 amino acids downstream of the mutation, p.Lys706Serfs*19. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PMS2 protein with potentially abnormal function. This sequence change has not been reported in population databases (gnomAD, ExAC). The p.Lys706Serfs*19 change has been reported in individuals with Lynch syndrome (PMID: 26110232, 23012243, 25856668, 28135145), constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 27001570, 27476653), and ovarian cancer (PMID: 26681312). Additionally, other frameshift deletions downstream of this sequence change in PMS2 have been described in patients with Lynch syndrome (PMIDs: 22081473, 24689082). These collective evidences suggest this is a pathogenic sequence change, however functional studies have not been performed to prove this conclusively. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2022 | 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 with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency syndrome in the published literature (Adam 2016, Bouffet 2016); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Goodenberger 2016, Suerink 2015, Yurgelun 2017, Wang 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 25856668, 26110232, 28514183, 28135145, 28152038, 23012243, 27001570, 27476653, 30322717, 32885271, 30787465, 31992580, 31447099) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 02, 2024 | The PMS2 c.2117del (p.Lys706Serfs*19) 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 individuals and/or families affected with Lynch syndrome (PMID: 26110232 (2016), 28135145 (2017), 31992580 (2020)), colorectal cancer (PMID: 25856668 (2015)), ovarian cancer (PMID: 26681312 (2015), 30322717 (2018)), and breast cancer (PMID: 32885271 (2021)). This variant has also been reported in a homozygous and compound heterozygous state in individuals affected with Constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 27001570 (2016), 34308104 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2022 | The c.2117delA pathogenic mutation, located in coding exon 12 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 2117, causing a translational frameshift with a predicted alternate stop codon (p.K706Sfs*19). This alteration has been reported in an individual diagnosed with transverse colon cancer at the age of 53, whose tumor was MSI-H, as well as in a healthy individual at the age of 64 (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). It has also been reported in multiple individuals from a Lynch syndrome family (Suerink M et al. Genet. Med. 2016 Apr;18:405-9). In addition, two siblings with diagnoses of constitutional mismatch repair (CMMRD) syndrome, both with recurrent diagnoses of glioblastoma multiforme, as well as café-au-lait spots, were found to be homozygous for this alteration (Bouffet E et al. J. Clin. Oncol. 2016 Jul;34:2206-11). 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 | Feb 17, 2023 | This variant deletes 1 nucleotide in exon 12 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An RNA study has indicated that the variant transcript is not stably expressed (PMID: 26110232). This variant has been reported in individuals affected with Lynch syndrome (PMID: 23012243, 25856668, 26110232) and ovarian cancer (PMID: 26681312), This variant also have been detected in compound heterozygosity and in homozygosity in two individuals affect with constitutional mismatch repair deficiency syndrome (PMID: 27001570, 27476653). 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. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 25, 2016 | - - |
PMS2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 29, 2024 | The PMS2 c.2117delA variant is predicted to result in a frameshift and premature protein termination (p.Lys706Serfs*19). This variant has been reported in the homozygous state in two siblings with mismatch repair deficiency (Bouffet et al. 2016. PubMed ID: 27001570), and in multiple patients with breast and/or ovarian cancer (Supplemental Table 1, Carter et al. 2018. PubMed ID: 30322717, Supplemental Tables, Lerner-Ellis et al. 2020. PubMed ID: 32885271; Table S1, Susswein et al. 2015. PubMed ID: 26681312), and also in patients with Lynch syndrome (Patient Ly-51, Wang et al. 2020. PubMed ID: 31992580; Table A1, Yurgelun et al. 2017. PubMed ID: 28135145). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142765/). Frameshift 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 | Oct 17, 2022 | Variant summary: PMS2 c.2117delA (p.Lys706SerfsX19) 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 was absent in 226056 control chromosomes (gnomAD). c.2117delA has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Goodenberger_2015, Suerink_2016), while it was also reported in a 64 year-old unaffected individual (Goodenberger_2015). Furthermore, the variant was detected in homozygous siblings and in another compound heterozygous individual affected with constitutional MMR deficiency (Adam_2016, Bouffet_2016). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters (evaluation after 2014) cite 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 01, 2021 | The p.Lys706SerfsX19 variant in PMS2 has been reported in at least 6 individuals with Lynch syndrome-associated cancers (Vaughn 2013 PMID: 23012243, Goodenberger 2015 PMID: 25856668, Susswein 2016 PMID: 26681312, Yurgelun 2017 PMID: 28135145, Carter 2018 PMID: 30322717, Lerner-Ellis 2020 PMID: 32885271, Wang 2020 PMID: 31992580), as well as in 4 individuals from a family included in a study of pre-symptomatic and symptomatic variant carriers (Suerink 2016 PMID: 26110232, no clinical details provided). It has also been reported in the homozygous state in two siblings with constitutional mismatch repair deficiency syndrome (Bouffet 2016 PMID: 27001570). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 14276) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 706 and leads to a premature termination codon 19 amino acids downstream. This alteration is then 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_Supporting, PS4_Moderate. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Lys706Serfs*19) 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). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency, Lynch syndrome, and/or ovarian cancer (PMID: 23012243, 25856668, 26110232, 26681312, 27001570, 27476653, 28135145, 30322717, 30680046). ClinVar contains an entry for this variant (Variation ID: 142765). For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Lys706SerfsX19 variant was identified in 5 of 90280 proband chromosomes (frequency: 0.00005) from American individuals or families with CRC and unexplained adenomatous polyposis (Yurgelun 2017, Espenschied 2017, Adam 2016). In one study looking at glioblastomas, this variant was identified in homozygous state in 2 affected siblings with characteristics of CMMRD (Constitutional Mismatch Repair Deficiency) exhibiting café-au-lait spots and neurofibromatosis type 1 and glioblastoma tumors showing a higher mutation load than sporadic pediatric and adult gliomas (Bouffet 2016). In another study looking at unexplained FAP, 1 individual carried the variant with a co-occurring pathogenic PMS2 variant (c.1A>T [p.Met1?), confirming CMMRD (Adam 2016). The variant was also identified in dbSNP (ID: rs587782704) “With Pathogenic allele”, ClinVar (classified pathogenic by Ambry Genetics, GeneDx and Invitae), Clinvitae (3x), COGR (classified as pathogenic by 1 clinical laboratory), Insight Colon Cancer Gene Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The p.Lys706SerfsX19 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 706 and leads to a premature stop codon 19 codons downstream. 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 Lynch syndrome 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. - |
Hereditary cancer Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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