Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000075786 | SCV000106796 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability <0.001 |
Invitae | RCV000811318 | SCV000951578 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-02-03 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Ala21 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 14961575), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change retained PMS2 binding activity and some MLH1 protein function in yeast assays (PMID: 21404117). This variant has been observed in individuals and families affected with Lynch syndrome or constitutional mismatch repair deficiency (PMID: 21404117, 30013564). ClinVar contains an entry for this variant (Variation ID: 90297). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 21 of the MLH1 protein (p.Ala21Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. |