Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP3PP5
The NM_000535.7(PMS2):c.123_131del(p.Leu42_Glu44del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E41E) has been classified as Likely benign.
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000535.7
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM4
?
PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_000535.7.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-6005923-TTCTACTAAC-T is Pathogenic according to our data. Variant chr7-6005923-TTCTACTAAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216449.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=4, Uncertain_significance=1}.
Likely pathogenic, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Oct 14, 2019
The p.Leu42_Glu44del variant in MSH6 has been reported in 1 individual with suspected diagnosis of Lynch syndrome who also carried a variant of uncertain significance in ATM (Yurgelun 2015) and in an individual with constitutive mismatch repair deficiency in the compound heterozygous state (D'Arcy 2019). This variant has also been reported in ClinVar (ClinVar ID 216449), with conflicting interpretations. It was absent from large population studies. This variant is a deletion of 3 amino acids at position 42 and is not predicted to alter the protein reading-frame. In vitro functional studies provide some evidence that this variant impacts protein function (D'Arcy 2019); however, these types of assays may not accurately represent biological function. 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: PM2, PM3, PM4, PS3_Supporting. -
Likely pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Apr 10, 2023
This variant is a 3 amino acid deletion within the amino-terminal ATPase domain of the PMS2 protein. Functional studies have shown that this variant is defective for protein expression, mismatch repair activity and ATPase activity, and demonstrated increased microsatellite instability (PMID: 30653781, 35189042). Structural studies have also indicated the variant protein is disordered and prone to aggregation (PMID: 30653781). This variant has been reported in several individuals affected with Lynch syndrome associated cancers (PMID: 25980754; ClinVar accession: SCV000663563.3). This variant has also been observed in compound heterozygous state with a known pathogenic PMS2 variant in an individual affected with autosomal recessive constitutional mismatch repair disorder (PMID: 30653781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
May 23, 2023
This variant is a 3 amino acid deletion within the amino-terminal ATPase domain of the PMS2 protein. Functional studies have shown that this variant is defective for protein expression, mismatch repair activity and ATPase activity, and demonstrated increased microsatellite instability (PMID: 30653781, 35189042). Structural studies have also indicated the variant protein is disordered and prone to aggregation (PMID: 30653781). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; ClinVar SCV000663563.3). This variant has also been observed in compound heterozygous state with a known pathogenic PMS2 variant in an individual affected with autosomal recessive constitutional mismatch repair disorder (PMID: 30653781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 17, 2021
The c.123_131delGTTAGTAGA pathogenic mutation (also known as p.L42_E44del) is located in coding exon 2 of the PMS2 gene. This variant results from an in-frame deletion of 9 nucleotides at positions 123 to 131. This results in the deletion of three amino acids between codons 42 and 44. This alteration has been identified in three unrelated individuals with colorectal tumors that demonstrated isolated loss of PMS2 expression by IHC; two of these probands had a family history of colorectal cancer (Ambry internal data). Based on an internal structural assessment, this alteration disrupts critical ATP-binding residues (Ban C et al. Cell. 1999 Apr;97:85-97; Guarné A et al. EMBO J. 2001 Oct;20:5521-31; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). This variant has been reported in a cohort of healthy individuals undergoing population screening for genetic conditions (Grzymski JJ et al. Nature Med. 2020 Aug;26(8):1235-9). However, it was also identified in a patient with Constitutional Mismatch Repair Deficiency syndrome (CMMRD), who also had PMS2 mutation p.R802* in trans (D'Arcy BM et al. Hum. Mutat. 2019 Apr;40:458-471). D'Arcy et al. also demonstrated that this variant lacks in vitro mismatch repair and ATPase activities. These amino acid positions are well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012;7:e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Lynch syndrome 4 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Mar 13, 2018
- -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Feb 02, 2024
- -
Hereditary nonpolyposis colon cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 22, 2024
Variant summary: PMS2 c.123_131delGTTAGTAGA (p.Leu42_Glu44del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 1.4e-06 in 1458556 control chromosomes (gnomAD v4.1). c.123_131delGTTAGTAGA has been reported in the literature in one individual who had a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015). D'Arcy_2019 reported this variant an individual who was clinically diagnosed with constitutive mismatch repair deficiency syndrome (CMMRD) and was compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant ablated MMR capacity and ATPase activity (D'Arcy_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 30653781). ClinVar contains an entry for this variant (Variation ID: 216449). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Mar 10, 2020
In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein.; Published functional studies demonstrate a damaging effect: deficient mismatch repair activity, reduced protein expression, and absent ATPase activity (DArcy 2019); Observed in individuals with Lynch-associated cancer and/or polyps (Yurgelun 2015); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653781, 25980754, 32719484) -
This variant, c.123_131del, results in the deletion of 3 amino acid(s) of the PMS2 protein (p.Leu42_Glu44del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome and constitutive mismatch repair deficiency syndrome (PMID: 25980754, 30653781; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 216449). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PMS2 function (PMID: 30653781). For these reasons, this variant has been classified as Pathogenic. -