ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2521del (p.Trp841fs) (rs886039646)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255351 SCV000322576 likely pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing This deletion of one nucleotide in PMS2 is denoted c.2521delT at the cDNA level and p.Trp841GlyfsX10 (W841GfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCCC[delT]GGAA. The deletion causes a frameshift which changes a Tryptophan to a Glycine at codon 841, and creates a premature stop codon at position 10 of the new reading frame. Due to the position of the variant, nonsense-mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene disrupts a zinc binding motif (Fukui 2011) and includes several residues which are conserved across species. PMS2 c.2521delT has been reported as either homozygous or with a second PMS2 variant in individuals suspected of having Constitutional Mismatch Repair Deficiency syndrome (Bodo 2015, Mach?ckov? 2016). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Invitae RCV000552542 SCV000625623 pathogenic Hereditary nonpolyposis colon cancer 2019-12-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PMS2 gene (p.Trp841Glyfs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acids of the PMS2 protein. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed to co-occur with a second pathogenic PMS2 variant (c.2T>A) in an individual with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 30764633), and an individual affected with glioblastoma multiforme (PMID: 28218421). ClinVar contains an entry for this variant (Variation ID: 265586). This variant has been reported to affect PMS2 protein function (PMID: 26116798). This variant is expected to remove the C-terminal portion of the MLH1 interaction domain (amino acids 675-850), which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). This suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000564745 SCV000670737 pathogenic Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000722118 SCV000697352 likely pathogenic Turcot syndrome 2019-12-17 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2521delT (p.Trp841GlyfsX10) results in a premature termination codon in the last exon of the PMS2 mRNA, predicted to cause a truncation and disrupt the last 22 amino acids (Trp841-Asn862) of the PMS2 protein. The variant was absent in 177052 control chromosomes (in gnomAD). However, the variant c.2523G>A (p.Trp841X) has been observed in 64/10632 African alleles in gnomAD, including 3 homozygotes, suggesting loss of the far end of C-terminal of PMS2 protein (the last 22 amino acids Trp841-Asn862) is likely tolerable, although the technology utilized for this dataset does not rule out pseudogene interference and thus this data might not be relied upon. It was shown in an in vitro study that the C-terminal (amino acids 675-850) region of PMS2 is critical for PMS2-MLH1 dimerization , as the interaction was lost for the tested protein fragment truncated at amino acid 825 (Guerrette 1999), suggesting the region between amino acids 825-850 is critical for PMS2-MLH1 interaction. However, from these data the impact of truncation at amino acid 841 cannot be determined for the MLH1 interaction. The variant, c.2521delT, has been reported in the literature in two individuals affected with constitutional mismatch repair deficiency (CMMRD) syndrome. In one case it was found in homozygosity in a 4 years old patient diagnosed with high-grade glioma (Bodo 2015, Maletzki 2017), in the other case it was found in co-occurrence with the pathogenic PMS2 variant (c.2T>A (p.Met1Lys); Machackova 2016). The homozygous patient was from a consanguineous family, where three relatives were affected with Lynch syndrome- or CMMRD-associated cancers on the maternal side (they were diagnosed at the the age 5, 9 and 15 years). In functional studies performed on lymphoblastoid cell lines (LCLs) derived from the patient carrying the variant in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (while these changes couldn't be shown in LCLs from MMR-proficient controls, including Lynch syndrome patients; Bodo 2015). In another study, authors demonstrated MSI in the tumor obtained from the homozygous patient (Maletzki 2017). These results suggest that the variant is probably associated with the disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255351 SCV000884400 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing The PMS2 c.2521delT;p.Trp841fs variant has been published at least once in an individual with suspected constitutional mismatch repair deficiency syndrome, who also carried an additional pathogenic PMS2 variant (Machackova 2016). However, it was not determined if these variants were on opposite chromosomes or if the reportedly healthy parents of this individual carried either variant. The c.2521delT;p.Trp841fs variant is listed in the ClinVar database (Variation ID: 265586), but not in the dbSNP variant database or in the general population-based databases (Genome Aggregation Database, Exome Variant Server). This variant deletes one nucleotide and causes a frameshift. However, this variant only truncates 22 amino acids of unclear function (Guerrette 1999, Kondo 2001). Considering available information, this variant cannot be classified with certainty. References: Guerrette S et al. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem. 1999 Mar 5;274(10):6336-41. Kondo E et al. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res. 2001 Apr 15;29(8):1695-702. Machackova E et al. Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute. Klin Onkol. 2016;29 Suppl 1:S35-45.

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