ClinVar Genomic variation as it relates to human health

The MLH1 c.1559-?_1731+?del variant (Chr3:g.37081677-?_37083822+?del, GRCH7), results in a deletion of exons 14 and 15, although the precise breakpoints of this deletion were not determined, nor were the effects of this variant on the resulting mRNA or protein product. The variant was identified in 4 of 1449 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Dominguez-Valentin 2013, Pistorius 2007, Lagerstedt Robinson 2007, Wielandt 2012). One study reported MSI status of the proband’s tumor as positive and another study reported on MSI as being positive and MLH1 deficiency by IHC (Lagerstedt Robinson 2007, Wielandt 2012). The variant was also identified in Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database” (4x), InSight Colon Cancer Gene Variant Database (3x as class 5), ClinVar database (as pathogenic reviewed by an expert panel submitter: InSight), and UMD (1x with a “causal” classification). This variant was not identified in dbSNP, COSMIC, Zhejiang Colon Cancer Database (LOVD), “MMR Gene Unclassified Variants Database”, COGR database, the 1000 Genomes Project, HAPMAP, the NHLBI GO Exome Sequencing Project, the Genome Aggregation Database (Feb 27, 2017) and the Exome Aggregation Consortium database (August 8th 2016). This alteration is 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 this 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.