Submissions for variant NM_000535.7(PMS2):c.647G>T (p.Cys216Phe)

gnomAD frequency: 0.00001  dbSNP: rs730881908

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160882	SCV000211571	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a pediatric patient with B-cell acute lymphoblastic leukemia (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 11574484, 26580448)
Ambry Genetics	RCV000574055	SCV000663482	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-07	criteria provided, single submitter	clinical testing	The p.C216F variant (also known as c.647G>T), located in coding exon 6 of the PMS2 gene, results from a G to T substitution at nucleotide position 647. The cysteine at codon 216 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not 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	RCV000574055	SCV000691094	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 216 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 4/251492 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.
Invitae	RCV000629988	SCV000750944	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 216 of the PMS2 protein (p.Cys216Phe). This variant is present in population databases (rs730881908, gnomAD 0.004%). This missense change has been observed in individual(s) with B-Cell acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 182798). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000781737	SCV000920024	uncertain significance	not specified	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.647G>T (p.Cys216Phe) results in a non-conservative amino acid change located in the N-terminal DNA mismatch repair domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.647G>T has been reported in the literature in a child affected with B-Cell Acute Lymphoblastic Leukemia (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (PALB2 c.1317delG, p.Phe440fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genetic Services Laboratory, University of Chicago	RCV000781737	SCV002069632	uncertain significance	not specified	2020-09-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.647G>T, in exon 6 that results in an amino acid change, p.Cys216Phe. This sequence change has been described in the gnomAD database in four individuals with an overall population frequency of 0.002% (dbSNP rs730881908). The p.Cys216Phe change has been reported in one individual with B-cell acute lymphoblastic leukemia (PMID: 26580448). The p.Cys216Phe change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys216Phe substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys216Phe change remains unknown at this time.