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

gnomAD frequency: 0.00001  dbSNP: rs730881915

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656942	SCV000211585	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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, 30161022, 30877237, 31422818, 27535533)
Ambry Genetics	RCV000567463	SCV000674263	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-21	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). This alteration was observed in conjunction with a pathogenic PMS2 alteration in a patient diagnosed with colon cancer at age 16; the tumor had high microsatellite instability and equivocal PMS2 expression on IHC (Ambry internal data). 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, Mass General Brigham 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	Lynch syndrome 4	2018-04-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656942	SCV000889623	likely pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant has been reported in individuals with a Lynch Syndrome related cancer (PMID: 27978560 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Invitae	RCV001316571	SCV001507200	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 72 of the PMS2 protein (p.Gly72Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with colorectal cancer and uterine cancer (PMID: 27978560; Invitae). ClinVar contains an entry for this variant (Variation ID: 182808). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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.
Myriad Genetics, Inc.	RCV000663221	SCV004019831	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Color Diagnostics, LLC DBA Color Health	RCV000567463	SCV004359704	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 72 in the ATPase domain of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer, including those with abnormal immunohistochemistry results and microsatellite instability (PMID: 27978560, ClinVar: SCV000674263). This variant was detected in one individual affected with colorectal cancer who exhibited normal immunohistochemistry and microsatellite stability (ClinVar: SCV000674263). 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.