Submissions for variant NM_000535.7(PMS2):c.89A>G (p.Gln30Arg)

gnomAD frequency: 0.00001  dbSNP: rs56203955

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164904	SCV000215592	likely benign	Hereditary cancer-predisposing syndrome	2019-03-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000198290	SCV000254619	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 185474). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs56203955, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 30 of the PMS2 protein (p.Gln30Arg).
Counsyl	RCV000410641	SCV000489607	uncertain significance	Lynch syndrome 4	2016-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000482199	SCV000571957	uncertain significance	not provided	2016-10-10	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.89A>G at the cDNA level, p.Gln30Arg (Q30R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln30Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln30Arg occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Gln30Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000164904	SCV000909683	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 30 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 not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/245770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV002247569	SCV002519147	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410641	SCV004019849	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.
Baylor Genetics	RCV000410641	SCV004207859	uncertain significance	Lynch syndrome 4	2023-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482199	SCV004219031	uncertain significance	not provided	2022-07-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000041 (1/245770 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in 8 individuals with breast cancer as well as in 2 healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). 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, we are unable to determine the clinical significance of this variant.