rs587781281
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The ENST00000265849.12(PMS2):c.874A>T(p.Ile292Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I292V) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000265849.12 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.874A>T | p.Ile292Phe | missense_variant | 8/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.874A>T | p.Ile292Phe | missense_variant | 8/15 | 1 | NM_000535.7 | ENSP00000265849 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461652Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727166
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2021 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 140792). 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 isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 292 of the PMS2 protein (p.Ile292Phe). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2019 | The p.I292F variant (also known as c.874A>T), located in coding exon 8 of the PMS2 gene, results from an A to T substitution at nucleotide position 874. The isoleucine at codon 292 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. - |
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at