rs587782710
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.746_753delACTCCGTG(p.Asp249fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
PMS2
NM_000535.7 frameshift
NM_000535.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.77
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]
Genome browser will be placed here
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 7-5997375-ACACGGAGT-A is Pathogenic according to our data. Variant chr7-5997375-ACACGGAGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5997375-ACACGGAGT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.746_753delACTCCGTG | p.Asp249fs | 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.746_753delACTCCGTG | p.Asp249fs | frameshift_variant | 7/15 | 1 | NM_000535.7 | ENSP00000265849.7 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 genomes
Cov.:
29
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456526Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 725000
GnomAD4 exome
AF:
AC:
1
AN:
1456526
Hom.:
AF XY:
AC XY:
0
AN XY:
725000
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 29
GnomAD4 genome
Cov.:
29
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Asp249Valfs*2 variant was identified in 3 of 3382 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome (Talseth-Palmer 2016, van der Klift 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs587782710) as “With Pathogenic allele”, ClinVar and Clinvitae (as pathogenic by Ambry Genetics and Invitae), and Insight Hereditary Tumors Database (4x). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.746_753del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 249 and leads to a premature stop codon at position 250. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 24, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2023 | 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Talseth-Palmer et al., 2010; Yurgelun et al., 2015; Goodenberger et al., 2016; Wang et al., 2020); 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: 20487569, 25856668, 27064304, 28514183, 27435373, 30787465, 31992580, 25980754) - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2014 | The c.746_753del8 pathogenic mutation located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a patient with colorectal cancer diagnosed at age 38 (Talseth-Palmer BA et al. Hered Cancer Clin Pract 2010; 8:5). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2021 | The c.746_753delACTCCGTG pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon (p.D249Vfs*2). This mutation has been reported in multiple individuals with a personal and/or family history of HNPCC/Lynch syndrome-associated cancers (Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). This mutation has also been detected in conjunction with a second PMS2 mutation in patients with features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Guerrini-Rousseau L et al. Neurooncol Adv Dec;1:vdz033; Ambry internal data). 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 | Mar 21, 2022 | This variant deletes 8 nucleotides in exon 7 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. This variant has been reported in individuals affected with or suspected of having Lynch syndrome or constitutional mismatch repair deficiency (PMID: 20487569, 25980754, 27064304, 27435373, 32642664). 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. - |
Lynch syndrome 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 20, 2023 | - - |
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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Asp249Valfs*2) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and suspected Lynch syndrome (PMID: 20487569, 25980754, 27064304, 27435373). ClinVar contains an entry for this variant (Variation ID: 142778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at