Submissions for variant NM_000535.7(PMS2):c.733C>A (p.Leu245Met)

gnomAD frequency: 0.00001  dbSNP: rs201375580

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457456	SCV000552035	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 245 of the PMS2 protein (p.Leu245Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 41719). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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.
GeneDx	RCV000034635	SCV000566385	uncertain significance	not provided	2016-03-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.733C>A at the cDNA level, p.Leu245Met (L245M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Leu245Met 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 Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu245Met occurs at a position that is not conserved and is located within the ATPase domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Leu245Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001026290	SCV001188639	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The p.L245M variant (also known as c.733C>A), located in coding exon 7 of the PMS2 gene, results from a C to A substitution at nucleotide position 733. The leucine at codon 245 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001026290	SCV001354719	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 245 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 hereditary cancer in the literature. This variant has been identified in 1/246016 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034635	SCV000043433	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.