Table VI.
Variants defined as 'likely pathogenic'.
| Variants | Gene | ID Cancer (age onset) Familial history (Segregation analysis) | Somatic dMMR | The Genome Aggregation Database (GnomAD) | Exome Aggregation Consortium (ExAC) | 1000 Genomes Project | Additional information | ACMG Criteria (a) | New classification variant | INSIGHT/CLINVAR |
|---|---|---|---|---|---|---|---|---|---|---|
| c.376T>A p.(Tyr126Asn) | MLH1 | 19.39 endometrial (26) Not affected- (N.D.) BG |
MS1-HNO
MLH1 NO PMS2 |
0.00004 | 0.00007 | 0.00020 | This variant is located in the N-terminal ATPase domain | PS3.PM1, PP2, PP3, PP4 | Likely pathogenic | Reported as VUS, as pathogenic and six times as benign/VUS |
| c.470T>C p.(Val157Ala) | MLH3 | 18.17 breast and colon (37, 38) other affected-breast and colon (N.D.) AC | MS1-H | No frequency | No frequency | No frequency | The valine residue is highly conserved. | PS3, PM2, PP2, PP3, PP4 | Likely pathogenic | Not reported/VUS |
| c.3440A>T p.(Asn1147Ile) | MLH3 | 17.14 colon (52) other affected- endometrial and colon (N.D.) AC | MS1-H | 0.00040 | 0.00044 | 0.00060 | No relevant information | PS3, PP2, PP3, PP4 | Likely pathogenic | Not reported/conflicting interpretation |
| c.1178G>T p.(Trp393Leu) | ATM | 19.24 colon (29) other affected-endometrial and gastric (N.D.) AC | ND | No frequency | No frequency | No frequency | No information | PM2, PM5, PP2, PP3, PP4 | Likely pathogenic | Not reported |
| c.911T>C p.(Met304Thr) | CHEK2 | 11.33 sigma (51) other affected- colon (also in affected brother) AC | MS1-H | No frequency | No frequency | No frequency | The methionine residue is highly conserved. This variant has been reported to affect CHEK2 protein function (PMID: 30851065). | PM2.PP1, PP2, PP3, PP4 | Likely pathogenic | Not reported/VUS |
| c.1253C>T p.(Ser418Phe) | PMS2 | 10.17 colon (49) other affected-colon (also in affected brother) AC |
MSI-H NO
MLH1 NO PMS2 |
No frequency | No frequency | No frequency | The seine residue is moderately conserved. | PS3, PM2, PP2, PP3, PP4 | Likely pathogenic | Not reported/VUS |
| c.589-9_589-6delGTTT | MLH1 | 18.08 Colon (18) other affected-colon and pancreas (also in affected father and two uncle) BG | MSI-H | No frequency | No frequency | No frequency | This variant could affect mRNA splicing (HSF software) | PS3, PM2, PP3, PP4 | Likely pathogenic | Reported seven times as VUS/conflicting interpretation |
| c.2149G>A p.Val717Met | PMS2 | 19.46 Colon (38) not affected-(N.D.) BG |
MSI-H NO
MLH1 NO PMS2 |
0.00076 | 0.00091 | 0.00020 | The variant is located within the MutL C-terminal, and dimerisation functional domain. | PS3, PM2, PP3, PP4 | Likely pathogenic | Not reported/conflicting interpretation |
PS, strong evidence of pathogenicity (class 1-4); PM, moderate evidence of pathogenicity (class 1-6); PP, Supporting evidence of pathogenicity (class 1-5); adapted from Ref (45). dMMR, deficient mismatch repair; N.D., not determined; BG, Bethesda guidelines; AC, Amsterdam criteria; VUS, variants of uncertain significance.