ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.215G>A (p.Gly72Glu) (rs730881915)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656942 SCV000211585 uncertain significance not provided 2021-06-16 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with mismatch repair (MMR)-deficient colon cancer and segregated with disease in one family (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560, 11574484, 27535533, 30161022, 30877237, 31422818)
Invitae RCV000168187 SCV000218851 uncertain significance Lynch syndrome 2016-03-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 72 of the PMS2 protein (p.Gly72Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 182808). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000567463 SCV000674263 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-17 criteria provided, single submitter clinical testing The p.G72E variant (also known as c.215G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 215. The glycine at codon 72 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been observed in several individuals whose colorectal tumors demonstrated high microsatellite instability and/or loss of PMS2 expression on immunohistochemistry (IHC); however, this alteration has also been observed in an individual whose colorectal tumor was microsatellite stable and demonstrated normal mismatch repair protein expression on IHC (Ambry internal data; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Based on internal structural analysis using published crystal structures, this alteration leads to destabilization of the N-terminal ATPase domain (Guarné A et al. EMBO J. 2001 Oct;20:5521-31). This alteration was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168187 SCV000731350 likely pathogenic Lynch syndrome 2020-02-07 criteria provided, single submitter clinical testing The p.Gly72Glu variant in PM2 has been reported in 4 individuals with Lynch syndrome associated cancers such as colorectal cancer and segregated with disease in 1 affected individual from (Pearlman 2017, GeneDx per. Comm., Ambry per. Comm., Invitae per. Comm., LMM data, ClinVar Variation ID: 182808). In addition, tumors sampled from 3 of these individuals showed either high microsatellite instability or lacked PMS2 expression, while 1 tumor showed normal PMS2 expression. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the 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 based on case observations, absence from the general population, and functional and computational evidence. ACMG/AMP Criteria applied: PS4_supporting, PM2, PS3.
Counsyl RCV000663221 SCV000786411 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-04-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656942 SCV000889623 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Invitae RCV001316571 SCV001507200 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 72 of the PMS2 protein (p.Gly72Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 182808). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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