Submissions for variant NM_000535.7(PMS2):c.1271T>C (p.Phe424Ser)

dbSNP: rs876661186

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767177	SCV000279745	uncertain significance	not provided	2015-12-31	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1271T>C at the cDNA level, p.Phe424Ser (F424S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe424Ser 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 Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Phe424Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Phe424Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218654	SCV000601813	uncertain significance	not specified	2017-04-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573020	SCV000676164	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	clinical testing	The p.F424S variant (also known as c.1271T>C), located in coding exon 11 of the PMS2 gene, results from a T to C substitution at nucleotide position 1271. The phenylalanine at codon 424 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000708983	SCV000838179	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV001048582	SCV001212595	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-10	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) 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. ClinVar contains an entry for this variant (Variation ID: 234733). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the PMS2 protein (p.Phe424Ser).
Baylor Genetics	RCV003469112	SCV004205486	uncertain significance	Lynch syndrome 4	2023-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708983	SCV004833698	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 424 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 not been identified 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.