Table 3.
Evaluation of the impact of the detected TP53 and ARID1A mutations based on databases, in silico prediction pipeline, immunohistochemistry and functional assay.
| Gene | Variant | exon | VAF % |
Type | ClinVar | Cosmic |
in silico‡ prediction |
IHC§ | Functional assays | Overall evaluated pathogenicity |
|---|---|---|---|---|---|---|---|---|---|---|
| ARID1A | p.Q583X | 3 | 14 | nonsense | novel | novel | NA | 10 | NA | pathogenic |
| p.Q1188X† | 14 | 18 | nonsense | novel | pathogenic | NA | 5 | NA | pathogenic | |
| p.K1230Mfs | 14 | 22 | fs | novel | novel | NA | 25 | NA | pathogenic | |
| p.P1618S† | 18 | 22 | missense | novel | pathogenic | benign (5/14) | 5 | NA | likely pathogenic | |
| p.R1721X | 20 | 19 | nonsense | novel | pathogenic | NA | <1 | NA | pathogenic | |
| p.E1779G | 20 | 46 | missense | NA | novel | benign (1/14) | 80 | NA | likely benign | |
| p.Q1894X | 20 | 61 | nonsense | novel | pathogenic | NA | 3 | NA | pathogenic | |
| p.V2244G | 20 | 18 | missense | novel | pathogenic | benign (6/14) | 30 | NA | likely pathogenic | |
| TP53 | p.P80S | 4 | 29 | missense | VUS | novel | benign (4/14) | wt | wt | likely benign |
| p.L194P | 6 | 76 | missense | VUS | novel | patho (11/14) | aberrant | deleterious | pathogenic | |
| p.R196X | 6 | 6 | nonsense | pathogenic | pathogenic | NA | wt | NA | pathogenic | |
| p.R273P | 8 | 62 | missense | patho/likely patho | novel | patho (12/14) | aberrant | deleterious | pathogenic | |
| p.G245D | 7 | 70 | missense | patho/likely patho | novel | patho (12/14) | aberrant | deleterious | pathogenic | |
| p.R280K | 8 | 60 | missense | VUS | novel | patho (12/14) | aberrant | deleterious | pathogenic | |
| c.75–1G>T | i2 | 19 | splice | novel | novel | NA | wt + aberrant clone | NA | likely pathogenic | |
| c.782 + 1G>C | i7 | 16 | splice | novel | pathogenic | NA | wt | NA | likely pathogenic | |
| c.919 + 1G>A | i8 | 60 | splice | novel | pathogenic | NA | wt | NA | likely pathogenic |
†Mutations detected in the same melanoma sample, ‡in the brackets is the number of predictors assessing mutation as pathogenic out of the 14 predictors used, final evaluation by in silico predictors was considered pathogenic when more than seven predictors suggested pathogenicity of mutation, §evaluation of ARID1A expression shows the percentage of tumor cells with nuclear staining of any intensity, TP53 was evaluated as aberrant or wild-type, fs – frameshift, NA – not evaluated (recorded in the Clinvar database, but the clinical significance is not provided), wt – normal expression pattern or functional behavior compared to wt protein, VAF – variant allele frequency.