rs776688670
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000535.7(PMS2):βc.846_848delβ(p.Arg282del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. R282R) has been classified as Likely benign.
Frequency
Consequence
NM_000535.7 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.846_848del | p.Arg282del | inframe_deletion | 8/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.846_848del | p.Arg282del | inframe_deletion | 8/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461672Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727160
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This variant, c.846_848del, results in the deletion of 1 amino acid(s) of the PMS2 protein (p.Arg282del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776688670, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2021 | The c.846_848delGAG variant (also known as p.R282del) is located in coding exon 8 of the PMS2 gene. This variant results from an in-frame GAG deletion at nucleotide positions 846 to 848. This results in the in-frame deletion of an arginine at codon 282. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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