ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2095G>C (p.Asp699His) (rs587781317)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129052 SCV000183747 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000214144 SCV000279148 likely pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2095G>C at the cDNA level, p.Asp699His (D699H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). This variant was observed in a homozygous state, in a case of constitutional mismatch repair deficiency syndrome (CMMR-D) (Walter 2013) and was also identified in an individual undergoing PMS2 analysis whose tumor showed loss of PMS2 protein (Vaughn 2010). In vitro functional studies demonstrated intact RNA expression and protein expression and borderline deficient viability and DNA damage response, leading authors to classify this variant as moderately functional (Arora 2017). PMS2 Asp699His was not observed in large population cohorts (Lek 2016). Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Asp699His occurs at a position that is conserved across species and is located in the within the endonuclease motif of the endonuclease domain (Kosinski 2008, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider PMS2 Asp699His to be a likely pathogenic variant.
Invitae RCV000234750 SCV000285101 likely pathogenic Hereditary nonpolyposis colon cancer 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 699 of the PMS2 protein (p.Asp699His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in the population databases (ExAC no frequency). However, the frequency data is considered unreliable due to the presence of a pseudogene that has strong homology to this region. This variant has been observed in individuals with Lynch syndrome (PMID: 20205264, 23012243, 28514183, Invitae). It has also been reported as homozygous in an individual with constitutional mismatch repair deficiency (PMID: 23729388). ClinVar contains an entry for this variant (Variation ID: 140847). This variant has been reported to have borderline reduced viability and DNA damage response (PMID: 28494185). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214144 SCV001134589 likely pathogenic not provided 2018-12-29 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality. Enriched in patients. Predicted to have a damaging effect on the protein. Results on protein functions were inconclusive.
Integrated Genetics/Laboratory Corporation of America RCV001192585 SCV001360816 uncertain significance not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2095G>C (p.Asp699His) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 221718 control chromosomes (gnomAD). c.2095G>C has been reported in the literature, including one patient whose tumors showed isolated loss of PMS2 by immunohistochemistry (Vaughn_2010), and in a child with constitutional mismatch repair deficiency who carried the variant in the homozygous state (Walter_2013). In addition, the variant has been reported in other patients being tested by various NGS cancer panels, without long-range PCR to confirm lack of pseudogene interference (Espenschied_2017, Goodenberger_2015, Mauer_2013, Roberts_2018). These data indicate that the variant may be associated with disease. An in vitro functional study showed the variant to have proficient RNA expression and protein expression, with reduced viability leading authors to described the variant as moderately functional (Arora_2017). Three ClinVar submissions (evaluation after 2014) cite the variant twice as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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