7-5989799-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000535.7(PMS2):c.1144+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
PMS2
NM_000535.7 splice_donor
NM_000535.7 splice_donor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.45
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 16 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.059868675 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-5989799-C-T is Pathogenic according to our data. Variant chr7-5989799-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1144+1G>A | splice_donor_variant | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1144+1G>A | splice_donor_variant | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251134Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135734
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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, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 03, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 28, 2020 | The PMS2 c.1144+1G>A variant (rs373885654) is reported in the literature in an individual with colorectal cancer (Jiang 2019) and an individual with breast cancer (Wang 2018). This variant is also reported in ClinVar (Variation ID: 162508). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 10, which is likely to negatively impact gene function. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Jiang W et al. Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. Int J Cancer. 2019;144(9):2161-2168. Wang YA et al. Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer. 2018;18(1):315. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2017 | This variant is denoted PMS2 c.1144+1G>A or IVS10+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 10 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in two individuals included in a population screening cohort, however personal and family cancer histories were not provided (Amendola 2015). Based on the current evidence, we consider this variant to be pathogenic. - |
Lynch syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 13, 2020 | The c.1144+1G>A variant in PMS2 has been reported in one individual with PMS2-associated cancer (Wu 2019). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 162508). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch Syndrome. ACMG/AMP Criteria applied: PVS1, PM2. - |
Likely pathogenic, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Lynch syndrome 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 20, 2023 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 02, 2020 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs373885654, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with colorectal cancer and a personal and/or family history of breast and/or ovarian cancer (PMID: 29566657, 30521064). ClinVar contains an entry for this variant (Variation ID: 162508). Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | The c.1144+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the PMS2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). 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 donor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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 missing amino acids is unknown; however, the impacted region is critical for protein function based on identification of genomic coding exon 10 deletions in Lynch syndrome families with many probands demonstrating isolated loss of PMS2 expression in their tumors by immunohistochemistry (van der Klift H et al. Genes Chromosomes Cancer. 2005 Oct;44:123-38; Senter L et al. Gastroenterology. 2008 Aug;135:419-428; Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Tomsic J et al. Clin. Genet. 2013 Mar;83:238-43; Brea-Fernandez AJ et al. Clin. Genet. 2014 Jun;85:583-8; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This variant was identified in a 51 year old Chinese male patient whose colorectal tumor demonstrated loss of MSH2 and PMS2 expression on immunohistochemistry (IHC) (Jiang W et al. Int. J. Cancer, 2019 05;144:2161-2168). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;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_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at