7-5978595-C-T
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000535.7(PMS2):c.2275+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000535.7 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.2275+1G>A | splice_donor_variant | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.2275+1G>A | splice_donor_variant | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1443332Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 718046
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2017 | This variant is denoted PMS2 c.2275+1G>A or IVS13+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 13 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least two individuals with Lynch-associated personal and family histories where tumor testing in both individuals reported microsatellite instability and immunohistochemistry showing the presence of MLH1 and the absence of PMS2 (van der Klift 2016). Based on the current evidence, we consider this variant to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2022 | The c.2275+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the PMS2 gene. This alteration has been identified in multiple individuals diagnosed with colorectal cancer that demonstrated microsatellite instability with absent PMS2 protein expression by immunohistochemistry (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179; Wang et al. J. Med. Genet. 2020 07;57(7):487-499), where subsequent RNA analysis demonstrated aberrant PMS2 splicing resulting in a premature termination codon (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Lynch syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 22, 2023 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at