rs63750490
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.1840A>T(p.Lys614*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000752 in 1,461,880 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 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 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:4
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 66 year old female with a personal history of uterine cancer and family history of colorectal cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
nonsense/frameshift -
The p.Lys614X variant in PMS2 has been reported in 4 heterozygous individuals with colon cancer and 2 homozygous individuals with colorectal cancer ad astrocytomas (Yurgelun 2015, Herkert 2011, Senter 2008, Gururangan 2008). It segregated with PMS2-related cancer in one relative (Gururangan 2008). This variant was absent from large population studies and was classified as pathogenic on September 5, 2013 by the ClinGen-approved inSIGHT expert panel (ClinVar ID 91318). This nonsense variant leads to a premature termination codon at position 614, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PS4_Supporting. -
This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). Tumor data from affected individuals has demonstrated loss of PMS2 protein via immunohistochemistry or high microsatellite instability (PMID: 17993636, 18809606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:3
The PMS2 c.1840A>T (p.Lys614*) variant causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in individuals and families with Lynch syndrome or Lynch-related cancers (PMIDs: 25980754 (2015), 18809606 (2008), 18602922 (2008), 17993636 (2008)), as well as in individuals with ovarian cancer (PMID: 31447099 (2019)) and breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
The PMS2 p.Lys614* variant was identified in 2 of 198 proband chromosomes (frequency: 0.01) from individuals or families with colorectal cancer (Senter 2008). The variant was also identified in 3 probands of consanguineous parents with constitutional mismatch repair deficiency syndrome (Baas 2013, Gururangan 2007). The variant was also identified in dbSNP (ID: rs63750490) as "With Pathogenic allele ", ClinVar (classified as Pathogenic by Invitae, Ambry Genetics, GeneDx, InSight and Color), Cosmic (1x in large intestine tissue), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (4x), databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Lys614* variant leads to a premature stop codon at position 614, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in PMS2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 18809606, 18602922, 25980754); Observed homozygous in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 17993636); 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: 25980754, 21376568, 25856668, 14574005, 22577899, 18809606, 25691505, 18602922, 31447099, 30787465, 33087929, 28888541, 36922933, 17993636) -
Hereditary cancer-predisposing syndrome Pathogenic:3
The p.K614* pathogenic mutation (also known as c.1840A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1840. This changes the amino acid from a lysine to a stop codon within coding exon 11. This mutation has been detected in colorectal and endometrial cancer patients whose tumors demonstrated isolated absence of PMS2 by immunohistochemistry (Senter L et al. Gastroenterology 2008 Aug;135(2):419-28). It has also been identified in a homozygous state in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome, including colorectal cancer and high grade astrocytoma before age 20y (Gururangan S et al. Neuro-oncology 2008 Feb;10(1):93-7). 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. -
This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). Tumor data from affected individuals has demonstrated loss of PMS2 protein via immunohistochemistry or high microsatellite instability (PMID: 17993636, 18809606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
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Lynch syndrome 4 Pathogenic:3
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The c.1840A>T (p.Lys614*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome related tumors (PMID 17993636, 18602922,25980754) or constitutional mismatch repair deficiency syndrome (PMID 17993636). Therefore, this c.1840A>T (p.Lys614*) variant is classified as pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.1840A>T (p.Lys614X) 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, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251450 control chromosomes. c.1840A>T has been reported in the literature in the heterozygous state in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and/or endometrial cancer (e.g. Senter_2008, Gururangan_2008, Yurgelun_2015). The variant has also been reported in the homozygous state in at least one individual affected by constitutional mismatch repair syndrome (e.g. Gururangan_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited 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.Lys614*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and colorectal cancer and/or endometrial cancer (PMID: 17993636, 18602922, 21376568, 22577899, 22692065, 25856668). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91318). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at