Submissions for variant NM_000535.7(PMS2):c.983A>G (p.Asp328Gly) (rs587782852)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132452	SCV000187546	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-28	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
GeneDx	RCV000656944	SCV000279136	uncertain significance	not provided	2018-07-06	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.983A>G at the cDNA level, p.Asp328Gly (D328G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was observed in at least one individual with endometrial cancer and another with colorectal cancer whose tumor demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (Clendenning 2013, Ring 2016). PMS2 Asp328Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Asp328Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000226690	SCV000285167	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glycine at codon 328 of the PMS2 protein (p.Asp328Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with endometrial cancer and in an individual with suspected Lynch syndrome (PMID: 27443514, 23017166). ClinVar contains an entry for this variant (Variation ID: 142960). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000411483	SCV000488354	uncertain significance	Hereditary nonpolyposis colorectal cancer type 4	2016-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory,University of Chicago	RCV000214828	SCV000596478	uncertain significance	not specified	2017-04-27	criteria provided, single submitter	clinical testing
Color	RCV000132452	SCV000686262	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000708988	SCV000838184	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000214828	SCV000918049	uncertain significance	not specified	2017-09-19	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.983A>G (p.Asp328Gly) variant involves the alteration of a conserved nucleotide located in the Ribosomal protein S5 domain 2-type fold (via Interpro) and 2/3 in silico tools (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 5/245954 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, this observation needs to be cautiously considered due to the technology used inability to detect between the PMS2 gene and its pseudogene. Multiple publications have cited the variant in affected individuals diagnosed with CrC or endometrial cancer (Clendenning_2013, Ring_2016), with limited available information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additonal information becomes available.