Submissions for variant NM_000535.7(PMS2):c.340C>T (p.Leu114Phe)

gnomAD frequency: 0.00010  dbSNP: rs757441871

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214977	SCV000277328	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-20	criteria provided, single submitter	clinical testing	The p.L114F variant (also known as c.340C>T), located in coding exon 4 of the PMS2 gene, results from a C to T substitution at nucleotide position 340. The leucine at codon 114 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000537717	SCV000625638	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 114 of the PMS2 protein (p.Leu114Phe). 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: 233032). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000214977	SCV000909677	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 114 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 4/266888 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.
GeneDx	RCV001552609	SCV001773323	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800570	SCV002046512	uncertain significance	not specified	2020-12-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000214977	SCV002530326	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
Baylor Genetics	RCV003469064	SCV004205433	uncertain significance	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998023	SCV004842123	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 114 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 4/266888 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.