Table 4. Variant classified during the pilot testing phase using the TP53-specific ACMG/AMP guidelines.
All variants were annotated in relation to the transcript NM_000546.5 and protein NP_000537.3.
| TP53 variant | ClinVar ID | ClinVar Classifications (September, 2019)* | Prior Variant Classifications^ | Dual Biocurator Classifications | TP53-specific ACMG/AMP Final Classifications | Final Criteria Applied | |
|---|---|---|---|---|---|---|---|
| Original ACMG/AMP Guidelines# | TP53-specific ACMG/AMP Guidelines% | ||||||
| c.1079G>C p.(Gly360Ala) | 142003 | B/LB | LB | B/VUS | LB | LB | BS1, BS3_Supporting, BP4 |
| c.883C>T p.(Pro295Ser) | 428862 | LB | LB | VUS | LB | VUS | BP4 |
| c.206C>G p.(Ala69Gly) | 230112 | LB | LB | VUS | VUS | VUS | PM2_Supporting, BP4 |
| c.1093C>T p.(His365Tyr) | 80708 | VUS | VUS | VUS | LB | LB | BS3, BP4 |
| c.403T>G p.(Cys135Gly) | 376563 | VUS | VUS | LP | VUS | LP | PS3, PM2_Supporting, PP3_Moderate |
| c.1000G>C p.(Gly334Arg) | 182969 | VUS | VUS | VUS | VUS | VUS | BS3, PP3, PS4_Supporting |
| c.532C>G p.(His178Asp) | 482223 | LP | NA | LP/P | LP/P | LP | PS3, PM2_supporting, PM6 PP3_Moderate |
| c.538G>A p.(Glu180Lys) | 245711 | LP | P | P | VUS | LP | PM2_Supporting, PP3, PS4_Supporting, PM6, PS3_Moderate |
| c.431A>T p.(Gln144Leu) | 376647 | LP | NA | VUS | VUS | VUS | PM2_Supporting, PS4_Supporting, BS3_Supporting |
| c.578A>C p.(His193Pro) | 376612 | LP | NA | P | P | P | PS3, PM6, PM2_Supporting, PP3_Moderate, PS4_Supporting |
| c.743G>T p.(Arg248Leu) | 230253 | LP | P | P/LP | LP | P | PS3, PM1, PM2_Supporting, PP3_Moderate, PS4_Supporting |
| c.97–1G>A | 638853 | LP | P | P | LP/P | P | PVS1_Strong, PM2_Supporting, PS4_Supporting |
| c.537T>A p.(His179Gln) | 406578 | P/LP | NA | P | P | LP | PM6, PS3, PM2_Supporting, PP3 |
| c.517G>A p.(Val173Met) | 233951 | P/LP | LP | P | LP/P | P | PS2, PS3, PM2_Supporting, PS4_Supporting, PP3 |
| c.743G>A p.(Arg248Gln) | 12356 | P/LP | P | P | LP | P | PS3, PM1, PP3, PS4, PS2 |
| c.818G>A p.(Arg273His) | 12366 | P/LP | P | P | P | P | PS3, PS2, PS4, PM1, PP3 |
| c.1031T>C p.(Leu344Pro) | 12375 | P | LP | P/LP | LP | P | PS3, PM2_Supporting, PP3_Moderate, PS4_Moderate |
| c.659A>G p.(Tyr220Cys) | 127819 | P | P | P | P | P | PS3, PP1_strong, PM6, PP3_Moderate, PS4_Moderate |
| c.742C>T p.(Arg248Trp) | 12347 | P | P | P | P | P | PS2, PS3, PP1_Strong, PM1, PS4, PP3_Moderate |
| c.993+1delG | 428898 | P | P | P | P | P | PVS1, PM2_Supporting, PS4_Supporting, PP1_Moderate |
| c.892G>T p.(Glu298*) | 93323 | P | P | P | P | P | PVS1, PM2_Supporting, PS4_Supporting |
| c.372C>A p.(Cys124*) | 458537 | P | NA | P | P | P | PVS1, PM6, PM2_Supporting |
| c.488A>G p.(Tyr163Cys) | 127814 | P | NA | LP/P | P | P | PS3, PS2_Moderate, PM2_Supporting, PP3_Moderate, PS4_Supporting |
| c.455C>T p.(Pro152Leu) | 142766 | P | P | P | LP/P | P | PS3, PP3_Moderate, PS4, PP1 |
| c.919+1G>A | 633606 | P | P | P | P | P | PVS1_Strong, PM6_Supporting, PM2_Supporting |
| c.733G>A p.(Gly245Ser) | 12365 | P | P | P | P | P | PS3, PM1, PP3, PS4 |
| c.869G>A p.(Arg290His) | 127825 | Conflicting | VUS | VUS | VUS | B | BS3, BP4, BS1, BS2_Supporting |
| c.847C>T p.(Arg283Cys) | 127824 | Conflicting | VUS | VUS | VUS | VUS | BS3, PP3 |
| c.1040C>A p.(Ala347Asp) | 43587 | Conflicting | P | P | LP/P | LP | PS3, PM2_Supporting, PP1_Moderate, PS4_Supporting |
| c.1120G>C p.(Gly374Arg) | 230269 | Conflicting | LB/VUS | LB/VUS | LB | LB | BS3, BP4 |
| c.1096T>G p.(Ser366Ala) | 135360 | Conflicting | LB/VUS | LB/VUS | LB | LB | BS3, BP4 |
| c.935C>G p.(Thr312Ser) | 141102 | Conflicting | LB/VUS | B/LB | B/LB | B | BS1, BS3, BP4 |
| c.892G>A p.(Glu298Lys) | 141483 | Conflicting | LB | LB | LB | LB | BP4, BS3 |
| c.704A>G p.(Asn235Ser) | 127821 | Conflicting | LB/VUS | VUS | B | B | BS1, BS3, BS4, BP4, BP2, BS2_Supporting |
| c.245C>T p.(Pro82Leu) | 182946 | Conflicting | LB/VUS | VUS | LB | LB | BS3, BP4 |
| c.28G>A p.(Val10Ile) | 127806 | Conflicting | LB/VUS | LB | LB/VUS | LB | BS3, BP4 |
| c.21T>A p.(Asp7Glu) | 140782 | Conflicting | LB | VUS | VUS | LB | PM2_Supporting, BS3, BP4 |
| c.145G>A p.(Asp49Asn) | 186363 | Conflicting | LB | VUS | LB | LB | BP4, BS3 |
| c.641A>G p.(His214Arg) | 376615 | Conflicting | LP | LP/P | LP | LP | PS3, PM2_Supporting, PS4_Supporting |
| c.217G>A p.(Val73Met) | 142386 | Conflicting | LB | VUS | LB/VUS | B | BS1, BS3, BP4 |
| c.139C>T p.(Pro47Ser) | 43588 | Conflicting | B | B/LB | B | B | BA1, BS3, BP4, BS2 |
| c.319T>C p.(Tyr107His) | 140786 | Conflicting | LB/VUS | LB/VUS | B | B | BA1, BP4, BS3_Supporting, BS2_Supporting |
| c.428T>C p.(Val143Ala) | 792574 | NA | NA | LP/P | LP | LP | PS3, PM6, PM2_Supporting, PP3 |
Abbreviations: B = Benign, LB = Likely benign, VUS = Variant of uncertain significance, LP = Likely pathogenic, P = Pathogenic, Conflicting = Conflicting interpretations of pathogenicity, NA = Not Available.
ClinVar assertions were documented in September 2019. Conflicting variants were those that spanned different clinically relevant classifications.
Assertions provided by VCEP members with variant nominations. Some variants were nominated by multiple members; some with conflicting assertions. Variants listed as “NA” were not nominated by a VCEP member.
Variants were assessed by two curators using the original ACMG/AMP guidelines and any curation assertions conflicts are noted.
Additional rule specifications after pilot testing are largely responsible for differences in classifications between the Biocurator TP53-specified Classifications and the Final TP53 VCEP Classifications.