rs876659480
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.2155C>T(p.Gln719*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000535.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000845 AC: 2AN: 236580Hom.: 0 AF XY: 0.0000156 AC XY: 2AN XY: 128580
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2AN: 1457298Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 724896
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The PMS2 c.2155C>T;p.Gln719Ter variant has been described in at least one family with a clinical diagnosis of Lynch syndrome (ten Broeke 2015). The variant is listed in the ClinVar database (Variation ID: 231993), but is not listed in the dbSNP variant database. The variant is listed in the Genome Aggregation Database with an allele frequency of 0.0008622 percent (2/231974 alleles). This variant introduces a premature termination codon and is predicted to result in a truncated or absent protein. Considering available information, this variant is classified as pathogenic. References: ten Broeke SW et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015 Feb 1;33(4):319-25. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25111426, 32782288, 25512458, 26110232, 31948886, 27435373, 24362816, 21376568, 35734982) -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.2155C>T (p.Gln719X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.6e-06 in 231974 control chromosomes (gnomAD). c.2155C>T has been reported in the literature in individuals affected with Lynch Syndrome (Suerink 2015, ten Broeke 2015, van der Klift 2016), where in two patients the associated tumors lacked the PMS2 protein and displayed microsatellite instability (van der Klift 2016). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence, demonstrating the lack of mRNA, probably due to NMD (Suerink 2015, van der Klift 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln719*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome and/or prostate cancer (PMID: 25512458, 31948886). ClinVar contains an entry for this variant (Variation ID: 231993). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.Q719* pathogenic mutation (also known as c.2155C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2155. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation was reported in one family from a cohort of 98 PMS2 positive families (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb; 33(4):319-25). This mutation was also reported in two Dutch probands diagnosed at ages 44 and 57 with MSI-H colorectal cancer and both tumors demonstrated loss of PMS2 expression by immunohistochemistry (van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179). In a cohort of European PMS2 mutation carriers, this variant was identified in three carriers (3/381) from two different families (2/130) (Suerink M et al. Genet Med, 2016 Apr;18:405-9). This mutation was also reported as homozygous in a 19 year old male proband diagnosed with colorectal cancer and leukemia in addition to having a family history of cancer (Arslan Ates E et al. Medeni Med J, 2022 Jun;37:150-158). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Lynch syndrome 4 Pathogenic:1
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at