chr7-6004002-C-G
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000535.7(PMS2):c.220G>C(p.Gly74Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.220G>C | p.Gly74Arg | missense_variant | 3/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.220G>C | p.Gly74Arg | missense_variant | 3/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 27
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 04, 2023 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant has been reported in individuals with Lynch syndrome associated cancers. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2022 | 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484) - |
Lynch syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This missense variant replaces glycine with arginine at codon 74 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, however Gly74 is a highly conserved amino acid in the ATP binding motif (PMID: 11574484). This variant has been observed in multiple individuals affected with colorectal cancer. having tumors with high microsatellite instablility or lacking PMS2 signal using immunohistochemistry (ClinVar Variation ID: 486943; SCV000676191.4, SCV000751189.6). The variant has also been observed in an individual with constitutional mismatch repair syndrome (ClinVar Variation ID: 486943; SCV000676191.4). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 74 of the PMS2 protein (p.Gly74Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome and constitutional mismatch repair deficiency syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 486943). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2023 | The p.G74R variant (also known as c.220G>C), located in coding exon 3 of the PMS2 gene, results from a G to C substitution at nucleotide position 220. The glycine at codon 74 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in individuals whose colorectal tumors displayed high microsatellite instability (MSI-H) and either absent or weak PMS2 staining on immunohistochemistry (Ambry Internal Data). Based on an internal structural assessment, this alteration causes significant structural destabilization of the ATPase domain (Guarné A et al. EMBO J. 2001 Oct;20:5521-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Lynch syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at