ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

This sequence change creates a premature translational stop signal (p.Leu731Cysfs*3) 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 Lynch syndrome (PMID: 15872200, 20186688). ClinVar contains an entry for this variant (Variation ID: 91331). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 5 nucleotides in exon 13 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An RNA study suggests the unstable expression of the variant transcript (PMID: 20186688). This variant has been reported in at least 10 individuals affected with Lynch syndrome-associated cancers (PMID: 15256438, 15872200, 20186688, 22081473, 26845104, 27435373, 28874130, 30077346, 31942411, 31992580). 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.

PMS2: PVS1, PM2, PS4:Moderate

The c.2192_2196delTAACT pathogenic mutation, located in coding exon 13 of the PMS2 gene, results from a deletion of 5 nucleotides at nucleotide positions 2192 to 2196, causing a translational frameshift with a predicted alternate stop codon (p.L731Cfs*3). This mutation has been reported in several individuals diagnosed with early onset colon cancer whose tumors showed isolated loss of PMS2 by IHC and/or microsatellite instability (Nakagawa H et al. Cancer Res. 2004 Jul 15;64(14):4721-7; Hampel H et al. N. Engl. J. Med. 2005 May 5;352(18):1851-60; Senter L et al. Gastroenterology 2008 Aug;135(2):419-28; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Wang Q et al. J Med Genet, 2020 07;57:487-499). This mutation has also been reported in a patient with breast and ovarian cancer and a family history of breast and pancreatic cancer (Shirts BH et al. Genet. Med. 2016 10;18:974-81), as a germline mutation in an ovarian cancer patient with a microsatellite unstable tumor and family history of breast and/or ovarian cancer (Jorge S et al. Gynecol Oncol, 2020 03;156:517-522), and in 1/107 Macedonian individuals with a clinical history of hereditary polyposis or hereditary non-polyposis colorectal cancer who underwent multi-gene panel testing (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Of note, this alteration is also designated as c.2192_2196del5 in published literature. 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.

Frameshift 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 patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Nakagawa 2004, Senter 2008, Rossi 2017, Lee 2018, Wang 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 15256438, 18602922, 28874130, 30077346, 31992580, 20186688, 15872200, 16472587, 31447099, 29625052)

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

The p.Leu731CysfsX3 variant in PMS2 has been reported in at least 3 individuals with PMS2-associated cancers (Nakagawa 2004 PMID: 15256438, Hampel 2005 PMID: 15872200, van der Klift 2010 PMID: 20186688) and has been identified in 1/109826 European chromosomes by gnomAD (http://gnomAD.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 731 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in individuals with Lynch syndrome. Moreover, this variant has also been classified as Pathogenic on Jun 21, 2019 by the ClinGen approved InSiGHT expert panel in ClinVar (Variation ID: 91331). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.

Variant interpreted as Pathogenic and reported on 12-23-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.