Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076835 | SCV000108322 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
Ambry Genetics | RCV000164116 | SCV000214731 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-30 | criteria provided, single submitter | clinical testing | The p.Q643* pathogenic mutation (also known as c.1927C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1927. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been reported in multiple individuals with biallelic PMS2 mutations who presented with very early-onset brain tumors, small bowel cancers, and adenomas, whose tumors were microsatellite high and showed isolated loss of PMS2 protein expression (Agostini M et al. Am. J. Gastroenterol. 2005 Aug;100:1886-91; Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Pastrello C et al. Genet. Med. 2011 Feb;13:115-24). This mutation has also been reported in multiple individuals with apparently sporadic colon cancer that showed isolated absence of the PMS2 protein on immunohistochemistry (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). Of note, this mutation is also designated as c.1951C>T 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. |
Labcorp Genetics |
RCV000524452 | SCV000261552 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln643*) 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 Lynch syndrome, and constitutional mismatch repair deficiency syndrome (PMID: 6144131, 18602922, 20205264, 23012243, 26895986). ClinVar contains an entry for this variant (Variation ID: 91320). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000223612 | SCV000279560 | pathogenic | not provided | 2021-01-27 | criteria provided, single submitter | clinical testing | 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; Reported in multiple individuals with colorectal cancer whose tumors lacked PMS2 expression on immunohistochemistry (Senter 2008, Goodenberger 2016, Rosty 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) in patients with constitutional mismatch repair deficiency syndrome in published literature (Agostini 2005, Vaughn 2010); 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: 25525159, 26895986, 22658618, 28514183, 29489754, 25637381, 16740762, 21239990, 16144131, 18602922, 18709565, 25856668, 20205264, 21376568, 19283792, 20531397, 16283678, 30262806, 31447099, 31992580, 32231684, 31433215, 32719484, 30755392) |
Color Diagnostics, |
RCV000164116 | SCV000686167 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-11 | criteria provided, single submitter | clinical testing | 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 heterozygous carriers affected with colorectal cancer (PMID: 18602922, 26895986, 27273229, 31433215), as well as compound heterozygous carriers with phenotypes consistent with Turcot syndrome and constitutional mismatch repair deficiency syndrome (PMID: 16144131, 20205264). This variant has also been reported in an individual with breast cancer (PMID: 33753322). This variant has been identified in 1/251242 chromosomes 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323387 | SCV000697317 | pathogenic | Hereditary nonpolyposis colon cancer | 2023-07-06 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1927C>T (p.Gln643X) 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. The variant allele was found at a frequency of 4e-06 in 251280 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1927C>T, has been reported in the literature in numerous individuals affected with Lynch Syndrome (e.g., Senter_2008, Agostini_2005, Rosty_2016). The variant of interest has also been identified in compound heterozygous patients who have early-onset cancers, as well as in heterozygous colorectal cancer patients with a later age of onset than in compound heterozygotes (e.g., Pastrello_2011, Vaughn_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports a loss of PMS2 immunohistochemistry reactivity, suggesting that the transcript undergoes nonsense-mediated decay or the truncated protein product is unstable (e.g., Vaughn_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20205264, 21239990, 16283678, 22658618, 18602922, 16144131, 19283792, 26895986). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Laboratory for Molecular Medicine, |
RCV000076835 | SCV000731326 | pathogenic | Lynch syndrome | 2021-10-27 | criteria provided, single submitter | clinical testing | The p.Gln643X variant in PMS2 has been reported in at least 5 individuals with Lynch syndrome-associated cancers where most tumors lacked PMS2 expression on immunohistochemistry (Senter 2008 PMID: 18602922, Rosty 2016 PMID: 26895986, Okkels 2019 PMID: 31433215, Wang 2020 PMID: 31992580), and segregated with colorectal cancer in 1 affected relative (Agostini 2005 PMID: 16144131). It has also been reported in the compound heterozygous state in 2 individuals with early-onset cancers consistent with Turcot syndrome and in 2 individuals with clinical features of constitutional mismatch repair deficiency (CMMRD; Agostini 2005 PMID: 16144131, Vaughn 2010 PMID: 20205264, Grobner 2018 PMID: 29489754, Rusch 2018 PMID: 30262806). Additionally, this variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 643, 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 as well as autosomal recessive CMMRD. This variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91320). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting) and autosomal recessive CMMRD (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3). |
Center for Personalized Medicine, |
RCV000735282 | SCV000854435 | pathogenic | Pulmonary arterial hypertension; Respiratory insufficiency; Pulmonary valve insufficiency | criteria provided, single submitter | clinical testing | ||
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000223612 | SCV001134588 | pathogenic | not provided | 2019-04-14 | criteria provided, single submitter | clinical testing | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. |
Myriad Genetics, |
RCV003452988 | SCV004187678 | pathogenic | Lynch syndrome 4 | 2023-09-21 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
Baylor Genetics | RCV003452988 | SCV004207874 | pathogenic | Lynch syndrome 4 | 2024-03-27 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV000076835 | SCV004844119 | pathogenic | Lynch syndrome | 2024-02-05 | criteria provided, single submitter | clinical testing | 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 heterozygous carriers affected with colorectal cancer (PMID: 18602922, 26895986, 27273229, 31433215), as well as compound heterozygous carriers with phenotypes consistent with Turcot syndrome and constitutional mismatch repair deficiency syndrome (PMID: 16144131, 20205264). This variant has also been reported in an individual with breast cancer (PMID: 33753322). This variant has been identified in 1/251242 chromosomes 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. |
CSER _CC_NCGL, |
RCV000148733 | SCV000190468 | pathogenic | Mismatch repair cancer syndrome 1 | 2014-06-01 | no assertion criteria provided | research |