Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075275 | SCV000106268 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Ambry Genetics | RCV002390220 | SCV002703108 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-14 | criteria provided, single submitter | clinical testing | The p.Q537* pathogenic mutation (also known as c.1609C>T), located in coding exon 14 of the MLH1 gene, results from a C to T substitution at nucleotide position 1609. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This alteration has been reported in one Austrian HNPCC family (Wolf B et al. Wien. Klin. Wochenschr., 2005 Apr;117:269-77), as well as 1/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). 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. |
| Invitae | RCV002513801 | SCV003525419 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89801). This premature translational stop signal has been observed in individual(s) with autosomal dominant MLH1-related conditions (PMID: 15926618, 32283892). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln537*) 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). |
| Myriad Genetics, |
RCV003451039 | SCV004186457 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-20 | 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001354465 | SCV001549090 | pathogenic | not provided | no assertion criteria provided | clinical testing | The MLH1 p.Gln537* variant was identified in 1 of 738 proband chromosomes (frequency: 0.001) from Swedish individuals or families with Lynch syndrome (Lagerstedt-Robinson 2016). The variant was also identified in dbSNP (ID: rs63751277) “With Pathogenic allele”, and ClinVar (classified pathogenic, reviewed by an expert panel (2013); submitter InSIGHT). The variant was not identified in UMD-LSDB. 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 c.1609C>T variant leads to a premature stop codon at position 537 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome 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. |