Description
The MLH1 p.Ser44Phe variant was not identified in the literature in an affected population nor was it identified in the dbSNP, ClinVar, UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion/deletion, which is predicted to result in the substitution of a serine (Ser) residue for phenylalanine (Phe) at codon 44. This variant was identified by our laboratory in a patient with an MLH1- and PMS2-deficient endometrial tumour. The same missense variant resulting from a different nucleotide change (c.131C>T) has been reported in ClinVar as pathogenic (evaluated by an InSiGHT expert panel in 2013). The variant was demonstrated to reduce binding between MLH1 and PMS2 in an interaction assay (Guerrette 1999). Yeast cells expressing the equivalent missense variant (p.Ser41Phe) had increased mutation frequencies caused by MMR defects (Ellison 2001). The p.Ser44 residue is moderately conserved across species and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
