rs587780064
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000535.7(PMS2):c.989-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
PMS2
NM_000535.7 splice_acceptor, intron
NM_000535.7 splice_acceptor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.29
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.060254924 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 27, new splice context is: tgatatcaatgttactccAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-5989956-C-A is Pathogenic according to our data. Variant chr7-5989956-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 127802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5989956-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246764Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133430
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GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1427630Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 710880
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 25, 2024 | This variant causes a G to T nucleotide substitution at the -1 position of intron 9 of the PMS2 gene. RNA studies on patient-derived RNA and minigene splicing assay have shown that this variant resulted in aberrant mRNA predicted to cause in-frame deletion in the ATPase domain (PMID: 19039682, 26247049). This variant has been reported as homozygous in two siblings, one affected with Turcot syndrome and the other affected with colon cancer at age 19 (PMID: 19039682), as well as multiple individuals affected with Lynch syndrome-associated cancer (PMID: 19723918, 24790682) and colon polyps (PMID: 26681312). The majority of the tumors exhibited microsatellite instability and this variant is reported to segregate with disease (PMID: 24790682). This variant has been identified in 1/246764 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 13, 2020 | The c.989-1G>T variant in PMS2 has been reported in 6 probands with Lynch syndrome and segregated with disease in >15 affected individuals from 2 families (Grindedal 2009, Hansen 2014, Grindedal 2014, Susswein 2015, Carter 2018). This variant was also reported in one homozygous individual who had >8 Lynch-associated cancers, consistent with constitutional mismatch repair deficiency (Sjursen 2009). It was absent from large population studies, but reported in ClinVar (ClinVar ID 127802). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. RNA-based studies showed full or partial skipping of exon 10 (Hansen 2014, van der Klift 2015), and a study of microsatellite instability in carriers of this variant demonstrated that 19/23 cancers were microsatellite unstable, consitent with loss of protein function (Grindedal 2014). 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, PP1_Strong, PM2, PS4_Moderate, PS3_Supporting. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24689082, 25345868, 30322717, 25525159, 20587412, 19039682, 26247049, 24790682, 26681312, 29625052) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 29, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2021 | This variant causes a G to T nucleotide substitution at the -1 position of intron 9 of the PMS2 gene. RNA studies on patient-derived RNA and minigene splicing assay have shown that this variant resulted in aberrant mRNA predicted to cause in-frame deletion in the ATPase domain (PMID: 19039682, 26247049). This variant has been reported in a homozygous carrier affected with Turcot syndrome (PMID: 19039682) and multiple individuals affected with Lynch syndrome-associated cancer (PMID: 19723918, 24790682) and colon polyps (PMID: 26681312). The majority of the tumors exhibited microsatellite instability and this variant is reported to segregate with disease (PMID: 24790682). This variant has been identified in 1/246764 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 | Jun 14, 2022 | The c.989-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 10 of the PMS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected (Ambry internal data). This mutation has been detected in numerous individuals with Lynch syndrome and has been described as a founder mutation in the Norwegian population (Grindedal EM et al. Hered Cancer Clin Pract. 2014 Apr 21;12(1):12). It has also been detected in the homozygous state in a family with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (Sjursen W et al. Fam Cancer. 2009;8(3):179-86). Tumor analyses from affected individuals with this mutation have shown that the majority of tumors display microsatellite instability but normal PMS2 protein expression by immunohistochemistry. Functional analyses, using minigene assays and RT-PCR analyses of patient RNA, detected abnormal transcripts with partial or complete skipping of exon 10 (Sjursen W et al. Fam Cancer. 2009;8(3):179-86; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2024 | This sequence change affects an acceptor splice site in intron 9 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19039682, 19723918, 24790682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127802). Studies have shown that disruption of this splice site results in skipping of exon 10 and skipping of part of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 19039682, 26247049; internal data). For these reasons, this variant has been classified as Pathogenic. - |
Lynch syndrome 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 20, 2019 | This variant is located in the canonical splice acceptor site in intron 9 of the PMS2 gene and is predicted to lead to abnormal splicing. This variant is located at extremely low frequency in the gnomAD population database (1/246764 alleles). It has been reported in several Norwegian families affected with Lynch syndrome (PMID: 19039682, 24790682, 19723918), particularly cancers of the colon, endometrium, breast, stomach, and prostate. Interestingly, immunohistochemistry (IHC) studies of cancers with this variant were normal but they demonstrated microsatellite instability (MSI) (PMID: 24790682). In vitro functional studies show this variant leads to skipping of exon 10 which is part of an important functional domain of the protein product (PMID: 26247049). This PMS2 variant is thus considered pathogenic. - |
Lynch syndrome 1 Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
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
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -28
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at