Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_000535.7(PMS2):c.1714_1717delGCAAinsACAT(p.AlaThr572ThrSer) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. AT572AN*N?) has been classified as Pathogenic.
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]
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-5987047-GTT-CGTTTTAGTTG is described in ClinVar as [Pathogenic]. Clinvar id is 2674212.Status of the report is criteria_provided_single_submitter, 1 stars.
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Uncertain:2
Nov 08, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 17, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not specified Uncertain:1
Jan 10, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: PMS2 c.1714_1717delinsACAT (p.Ala572_Thr573delinsThrSer) results in an in-frame deletion-insertion that is predicted to delete/insert 2 amino acids from the protein. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. Nevertheless, the constituent variants of this deletion-insertion variant (i.e. c.1714G>A/p.Ala572Thr and c.1717A>T/p.Thr573Ser), are found to co-occur (and are likely part of the same haplotype) in at least some individuals in gnomAD v2.1.1, with the allele frequency being lower than the estimated maximal expected allele frequency for pathogenic variant in PMS2 causing Lynch Syncdrome phenotype (0.00011). However, control population data need to be cautiously considered since the variants lie within a region of the PMS2 gene that has high pseudogene homology. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1714G>A and c.1717A>T have been reported to co-occur in one individual affected with Lynch Syndrome (Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Apr 25, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In-frame deletion of 2 amino acids that are replaced by 2 different amino acids in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; Reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch-related cancer and/or polyps (PMID: 25980754); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17016615, 25980754) -