Submissions for variant NM_000535.7(PMS2):c.697C>G (p.Gln233Glu)

dbSNP: rs587779343

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212849	SCV000211573	uncertain significance	not provided	2014-07-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.697C>G at the cDNA level, p.Gln233Glu (Q233E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln233Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln233Glu occurs at a position that is highly conserved across species and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Gln233Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160884	SCV000216536	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.Q233E variant (also known as c.697C>G), located in coding exon 6 of the PMS2 gene, results from a C to G substitution at nucleotide position 697. The glutamine at codon 233 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000412005	SCV000489242	uncertain significance	Lynch syndrome 4	2016-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553589	SCV000625676	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 233 of the PMS2 protein (p.Gln233Glu). This variant is present in population databases (rs587779343, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182800). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824647	SCV002074368	uncertain significance	not specified	2022-01-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412005	SCV004019854	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.
All of Us Research Program, National Institutes of Health	RCV003998522	SCV004839930	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 233 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/282860 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.
Baylor Genetics	RCV000412005	SCV005056414	uncertain significance	Lynch syndrome 4	2024-02-28	criteria provided, single submitter	clinical testing