chr7-5982890-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000535.7(PMS2):c.2108C>A(p.Thr703Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,658 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. T703M) has been classified as Likely benign.
Frequency
Consequence
NM_000535.7 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 | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.2108C>A | p.Thr703Lys | missense_variant | 12/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.2108C>A | p.Thr703Lys | missense_variant | 12/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451658Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 721822
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2016 | This variant is denoted PMS2 c.2108C>A at the cDNA level, p.Thr703Lys (T703K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr703Lys 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 Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Thr703Lys occurs at a position that is not conserved and is located within the nuclease domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Thr703Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2016 | The p.T703K variant (also known as c.2108C>A), located in coding exon 12 of the PMS2 gene, results from a C to A substitution at nucleotide position 2108. The threonine at codon 703 is replaced by lysine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6475 samples (12950 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at