ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

ClinVar contains an entry for this variant (Variation ID: 89902). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 8521398, 10323887, 12362047, 15849733, 20587412). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln62*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).

The p.Q62* pathogenic mutation (also known as c.184C>T), located in coding exon 2 of the MLH1 gene, results from a C to T substitution at nucleotide position 184. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been identified in multiple individuals/families with suspected HNPCC/Lynch syndrome based on personal and/or family history (Bronner CE et al. Nature. 1994 Mar;368:258-61; Liu B et al. Nat. Genet. 1995 Jan;9:48-55; Wehner M et al. Hum. Mutat. 1997;10:241-4; Lamberti C et al. Gut. 1999 Jun;44:839-43; Kurzawski G et al. J. Med. Genet. 2002 Oct;39:E65; Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702). Several individuals with this mutation have been shown to have absent IHC staining for MLH1 in their tumors (Stormorken AT et al. J. Clin. Oncol. 2005 Jul;23:4705-12; Mangold E et al. J. Pathol. 2005 Dec;207:385-95; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85). One study also found that this mutation results in a non-functional protein in a yeast model in vivo assay (Tannergård P et al. Cancer Res. 1995 Dec;55:6092-6). 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.

MLH1: PVS1, PM2

This variant is denoted MLH1 c.184C>T at the cDNA level and p.Gln62Ter (Q62X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple families meeting Amsterdam Criteria and/or Bethesda Guidelines for Lynch syndrome (Liu 1995, Mangold 2005, Sjursen 2010) and is considered pathogenic.

Variant summary: MLH1 c.184C>T (p.Gln62X) 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 was absent in 246206 control chromosomes (in gnomAD). c.184C>T has been reported in the literature in multiple individuals from several families meeting Amsterdam Criteria for Lynch Syndrome (Lamberti 1999, Sjursen 2010). These data indicate that the variant is very likely to be associated with disease. In one of these studies it was experimentally confirmed that the variant of interest causes protein truncation (Lamberti 1999), moreover tumor IHC from several samples indicated missing MLH1/PMS2 protein (Sjursen 2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The MLH1 c.184C>T (p.Gln62*) variant causes the premature termination of MLH1 protein synthesis. This variant has been reported in the published literature in several affected individuals and families with colorectal cancer/Lynch Syndrome (PMIDs: 7704024 (1995), 8521398 (1995), 9298827 (1997), 10323887 (1999), 12362047 (2002), 15849733 (2005), 16216036 (2005), 16451135 (2006), and 20587412 (2010)). 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.