Table 3 Summary evaluation of conservation, structure and experimental results and application of classification criteria.
PMS2 protein variant (NP_000526.2) | MAPP/PP2 Prior probability of pathogenicity AlphaMissense prediction | ACMG classification of MAPP/PP2 prior | DeMaSk score | Conservation score1 | Evaluation of conservation and structure | Criteria applied based on experimental Results on RNA and protein level2 | Interpretation on functional level and classification2 | Variant classification2 | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
PMS2 | MLH1 | MutL | Average | ||||||||
p.Asp70Asn | 0.7383 | PP3 | -0,31 | 9 | 9 | 9 | 9 | Absolutely conserved in MutL, known role in function (ATP binding) | n.a. | Dysfunctional control variant (22;51) | n.a. (control variant) |
p.Asp286Gly | 0.7635 0.6286 | PP3 | -0,25 | 9 | 6 | 7 | 7 | Only conserved in PMS family proteins, role in formation of hydrophilic loop surface. Although non-conservative exchange, hydrophilic surface of loop is maintained by charged neighbor residues. | BS3 | Functional | BS1, BS3, BP5, PP3: Benign |
p.Asn335Ser | 0.6062 0.585 | Reaching no criteria | -0,30 | 9 | 9 | 9 | 9 | Absolutely conserved in MutL, known role in function (N-terminal dimerization) | PS3_moderate | Function compromised | BS1, PP4_moderate, PS3_moderate: VUS |
p.Ile679Thr | 0.5105 0.182 | Reaching no criteria | -0,24 | 8 | 9 | 7 | 8 | Hydrophobic residue absolutely conserved in MLH1 and PMS family. Contributes to hydrophobic core of dimerization interface. | PS3_moderate | Function compromised | PM2_supp, PS3_moderate: VUS |
p.Arg799Trp | 0.8917 0.7692 | PP3 _moderate | -0,34 | 9 | 7 | 5 | 7 | Only conserved in PMS family proteins. Surface residue. | BS3 | Functional | BA1, BS3, PP4_supp, PP3_moderate: Benign |
