ClinVar Genomic variation as it relates to human health

This variant is considered pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation.

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro731Leufs*52) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the MLH1 protein. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 22480969, 24733792). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 12799449, 16338176, 18566915, 20533529, 24802709, 27295708; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 135851).

The MLH1 p.Pro731LeufsX52 variant was identified in 5 of 548 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and Lynch Syndrome (Kurian 2014, Rouleau 2009). The variant was also identified in dbSNP (ID: rs587780683) as “with Pathogenic allele”, and in ClinVar as pathogenic by Invitae. The variant was further identified in the UMD-LSDB database 5X and listed as casual. The variant was not identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant databse, Zhejiang University database, Mismatch Repair Genes Variant database, and Insight Hereditary Tumors database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2190del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 731 and leads to a premature stop codon at position 782. This alteration is then predicted to result in 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.