Table 5.
Selected variants of interest in candidate melanoma susceptibility genes (excluding BRIP1, POLE and OCA2)
| Gene | Variant | Type | Allele count | MAF (AN = 976) |
MAF in ExAC1 / GoNL |
CADD | SIFT | Align GVGD2 | PolyPhen‐23 | UMD‐Predictor | FD | CoS4 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CBLB | c.770A>T, p.(His257Leu) | Missense | 1 | 0.0010025 | −/− | 33 | Delet. | C0 | Prob. Damaging | Pathogenic | Y | |
| CBLB | c.1402C>G, p.(Arg468Gly) | Missense | 1 | 0.0010025 | 0.000018/− | 23.6 | Delet. | C0 | Pos. Damaging | Pathogenic | Y | |
| ERCC3 | c.496G>A, p.(Val166Ile) | Missense | 1 | 0.0010025 | −/− | 24.6 | Delet. | C25 | Benign | Prob. Polymorphism | Y | |
| ERCC3 | c.847C>T, p.(Arg283Cys) | Missense | 5 | 0.005123 | 0.0014/0.002 | 34 | Delet. | C65 | Benign | Pathogenic | Y | N |
| ERCC3 | c.1421dup, p.(Asp474Glufs*2) | Frameshift | 1 | 0.0010025 | 0.00014/− | Y | ||||||
| ERCC3 | c.1776T>G, p.(Ile592Met) | Missense | 1 | 0.0010025 | −/− | 24.9 | Delet. | C0 | Prob. Damaging | Prob. Pathogenic | Y | |
| ERCC3 | c.2111C>T, p.(Ser704Leu) | Missense | 2 | 0.002049 | 0.0022/0.001 | 24 | Delet. | C15 | Benign | Pathogenic | N | N |
| MLLT6 | c.655C>T, p.(Arg219Trp) | Missense | 1 | 0.0010025 | 0.000064/− | 25.2 | Delet. | C15 | Pos. Damaging | Pathogenic | N | |
| MLLT6 | c.2195A>C, p.(Glu732Ala) | Missense | 1 | 0.0010025 | −/− | 24.6 | Delet. | C0 | Prob. Damaging | Pathogenic | Y | |
| MLLT6 | c.2755G>A, p.(Gly919Arg) | Missense | 1 | 0.0010025 | −/− | 26.2 | Delet. | C0 | Pos. Damaging | Pathogenic | N | |
| NEK2 | c.97‐2A>G | Splicing | 1 | 0.0010025 | 0.00029/− | Y | ||||||
| NEK2 | c.137A>G, p.(Glu46Gly) | Missense | 1 | 0.0010025 | −/− | 28 | Delet. | C0 | Prob. Damaging | Pathogenic | Y | N |
| NEK2 | c.952C>T, p.(Arg318*) | Nonsense | 1 | 0.0010025 | 0.000018/− | 39 | Pathogenic | Y | ||||
| NEK4 | c.500T>C, p.(Ile167Thr) | Missense | 1 | 0.0010025 | 0.000009/− | 26.9 | Delet. | C25 | Prob. Damaging | Pathogenic | Y | |
| NEK4 | c.1953_1955del, p.(Glu651del) | In‐frame Deletion |
1 | 0.0010025 | 0.0011/0.002 | N | ||||||
| NEK4 | c.2093+1G>C | Splicing | 1 | 0.0010025 | −/− | N | ||||||
| NEK10 | c.1094G>A, p.(Arg365Gln) | Missense | 7 | 0.007172 | 0.0094/0.009 | 25.2 | Delet. | C0 | Pos. Damaging | Polymorphism | N | Y |
| NEK11 | c.127G>C, p.(Val43Leu) | Missense | 2 | 0.002049 | 0.00016/−5 | 27.5 | Delet. | C25 | Pos. Damaging | Prob. Polymorphism | Y | |
| PARP1 | c.1814C>T, p.(Pro605Leu) | Missense | 1 | 0.0010025 | 0.000036/− | 22.6 | Delet. | C15 | Benign | Pathogenic | Y | |
| PARP1 | c.2656G>A, p.(Val886Met) | Missense | 1 | 0.0010025 | 0.000027/− | 32 | Delet. | C0 | Prob. Damaging | Pathogenic | Y | |
| POLH | c.626G>T, p.(Gly209Val) | Missense | 2 | 0.002049 | 0.0032/0.0035 | 28.1 | Delet. | C15 | Prob. Damaging | Prob. Polymorphism | Y | |
| POLH | c.890G>A, p.(Trp297*) | Nonsense | 1 | 0.0010025 | −/− | 40 | Pathogenic | Y | Y6 | |||
| RASEF | c.157C>T, p.(Arg53Trp) | Missense | 1 | 0.0010025 | 0.000049/− | 28.4 | Delet. | C0 | Prob. Damaging | Prob. Pathogenic | Y | |
| RASEF | c.1049_1050del, p.(His350Argfs*3) |
Frameshift | 1 | 0.0010025 | 0.000063/− | Y | ||||||
| RASEF | c.2078A>G, p.(Asp693Gly) | Missense | 1 | 0.0010025 | 0.000018/− | 32 | Delet. | C0 | Pos. Damaging | Pathogenic | Y | |
| RASEF | c.2207A>T, p.(Asn736Ile) | Missense | 1 | 0.0010025 | 0.000027/− | 27.4 | Delet. | C0 | Pos. Damaging | Pathogenic | Y |
Gene reference sequences: CBLB: NM_170662.4, ERCC3: NM_000122.1, MLLT6: NM_005937.3, NEK2: NM_002497.3, NEK4: NM_003157.5, NEK10: NM_152534.4, NEK11: NM_024800.4, PARP1: NM_001618.3, POLH: NM_006502.2, RASEF: NM_152573.3.
Abbreviations: AN, allele number, MAF, minor allele frequency, CADD, Combined Annotation Dependent Depletion, FD, in known functional domain, CoS, co‐segregation with melanoma in one or more families, Y, yes, N, no, Delet, deleterious, Pos, possibly, Prob, probably.
In European (non‐Finnish) population.
Possible classifications in Align GVGD are C0, C15, C25, C35, C45, C55 and C65. Variants in class C0 have the least probability of being pathogenic, variants in class C65 have the highest probability of being pathogenic. See also http://agvgd.hci.utah.edu/classifiers.php
HumVar trained PolyPhen‐2 model used for prediction.
Co‐segregation analyses of variants with melanoma phenotype: ERCC3 p.R283C: 1/2 (one family), ERCC3 p.S704L: 1/2 (one family), NEK2 p.E46G: 1/2, NEK10 p.R365Q: 2/2 (one family).
Common variant (MAF > 1%) in one or more non‐European populations.
The proband with the POLH p.W297* variant had a father with the recessively inherited disease xeroderma pigmentosum (MIM #278750) and he is therefore highly likely to have carried this variant as well.