ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1738A>T (p.Lys580Ter)

dbSNP: rs267608169
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076824 SCV000108311 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000129628 SCV000184421 pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing The p.K580* pathogenic mutation (also known as c.1738A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1738. This changes the amino acid from a lysine to a stop codon within coding exon 11. This mutation was detected in a patient diagnosed with cancer of the transverse colon at age 49, whose tumor showed isolated loss of PMS2 protein on IHC (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28). In addition, this mutation was observed along with another truncating PMS2 mutation in a patient with congenital mismatch repair deficiency syndrome who was diagnosed with high grade glioma at age 7 and lymphoblastic lymphoma at age 9 (Guerrini-Rousseau L et al. Neurooncol. Adv. 2019 Dec;1(1):vdz033). 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.
GeneDx RCV000260402 SCV000329709 pathogenic not provided 2023-07-06 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; Not observed 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: 28454591, 28514183, 18602922, 26895986, 25691505, 14574005, 31118792, 34178123, 30787465, 28888541, 31992580, 32782288, 35273153, 32719484, 31830689, 31433215, 32642664, 33259954)
Invitae RCV000524446 SCV000551932 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys580*) 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 colon cancer (PMID: 18602922). ClinVar contains an entry for this variant (Variation ID: 91312). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000129628 SCV001342490 pathogenic Hereditary cancer-predisposing syndrome 2023-02-08 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. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 18602922, 26895986, 31992580, 34285288). This variant also has been detected in individuals affected with constitutional mismatch repair deficiency syndrome as a homozygous mutation or as a heterozygous mutation in trans with a PMS2 truncation variant (PMID: 31433215, 32642664, 33259954). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307391 SCV002600400 pathogenic Hereditary nonpolyposis colon cancer 2022-10-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1738A>T (p.Lys580X) 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 251348 control chromosomes (gnomAD). c.1738A>T has been reported in the literature in multiple individuals affected with colorectal cancer, including cases where the tumor was confirmed to have high microsatellite instability (MSI-H) and/or absent PMS2 by immunohistochemistry (e.g. Senter_2008, Epenschied_2017, Gong_2019, Wang_2020) and in a compound heterozygous individual with constitutional mismatch repair deficiency (Okkels_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc. RCV003452986 SCV004187665 pathogenic Lynch syndrome 4 2023-09-20 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 RCV003452986 SCV004205358 pathogenic Lynch syndrome 4 2023-10-22 criteria provided, single submitter clinical testing

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