Description
This variant is denoted MLH1 c.188A>G at the cDNA level, p.Asp63Gly (D63G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, another variant at the same residue, MLH1 Asp63Glu, is considered pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT). MLH1 Asp63Glu has been reported to segregate with Lynch syndrome-related cancers in at least one family and has been shown to result in decreased MLH1 protein expression, deficient mismatch repair activity, and decreased nuclear localization of MLH1 and PMS2 (Raevaara 2005, Hardt 2011). MLH1 Asp63Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asp63Gly occurs at a position that is conserved across species and is located in the ATPase domain (Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MLH1 Asp63Gly to be a likely pathogenic variant.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
