Table 1.
Pathogenic/likely pathogenic germline variants in CDKN2A affecting p16INK4A, p14ARF transcripts and the associated neoplasms reported in the literature
| Effect on p14ARF (Transcript: NM_058195) | Effect on p16INK4A (Transcript: NM_000077) | Neoplasms reported in variant carriers | References | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Exon/ intron |
Nucleotide change | Protein change | Variant effect | Exon/ intron |
Nucleotide change | Protein change | Variant effect | MEL | PCa | NST | SARC | BrCa | HNSCC | LCa | NFB | Other neoplasms | |
| Ex 1β | Del of Exon 1 | – | null | – | – | – | – | / | uterine adenocarcinoma, thyroid adenomata, chest wall neurilemmoma, pituitary macroadenoma | [21, 25] | |||||||
| Ex 1β | c.47G > A | Gly16Asp | MS | – | – | – | – | / | [20] | ||||||||
| Ex 1β | c.60_61insCGGCCCGCCGCGAGTG | Val22Profs*46 | PT | – | – | – | – | / | [19] | ||||||||
| Ex 1β | c.97dup | Glu33Glyfs*30 | PT | – | – | – | – | Bladder ca. | [26] | ||||||||
| Ex 1β | c.161G > A | Arg54His | MS | – | – | – | – | / | [27] | ||||||||
| Ex 1β | c.193G > C | Gly65Arg | MS | – | – | – | – | / | / | [25, 28, 29] | |||||||
| In 1 | c.193 + 1G > A | n.d. | Splicea | – | – | – | – | / | [25, 27, 29–31] | ||||||||
| In 1 | c.194-3653G > T | n.d. | Int | Ex 1α | c.-34G > T | – | 5’UTR | / | [25, 29, 32–35] | ||||||||
| In 1 | c.194-3635dup | n.d. | Int | Ex 1α | c.-16_8dup | Ala4_Pro11dup b | In-frame INS | / | Multiple myeloma, brain tumor, colorectal ca. | [14, 36–40] | |||||||
| In 1 | c.194-3585C > A | n.d. | Int | Ex 1α | c.35C > A | Ser12* | PT | / | [41, 42] | ||||||||
| In 1 | c.194-3576G > A | n.d. | Int | Ex 1α | c.44G > A | Trp15* | PT | / | [25, 35, 42–44] | ||||||||
| In 1 | c.194-3573 T > G | n.d. | Int | Ex 1α | c.47 T > G | Leu16Arg | MS | / | / | [4, 25, 29, 45, 46] | |||||||
| In 1 | c.194-3573 T > C | n.d. | Int | Ex 1α | c.47 T > C | Leu16Pro | MS | / | / | [9, 45–48] | |||||||
| In 1 | c.194-3553G > A | n.d. | Int | Ex 1α | c.67G > A | Gly23Ser | MS | / | [45] | ||||||||
| In 1 | c.194-3552G > A | n.d. | Int | Ex 1α | c.68G > A | Gly23Asp | MS | / | [25, 48–51] | ||||||||
| In 1 | c.194-3549G > C | n.d. | Int | Ex 1α | c.71G > C | Arg24Pro | MS | / | / | / | [25, 32, 34, 51–53] | ||||||
| In 1 | c.194-3541G > T | n.d. | Int | Ex 1α | c.79G > T | Glu27* | PT | / | Neuroblastoma | [25, 54, 55] | |||||||
| In 1 | c.194-3525 T > C | n.d. | Int | Ex 1α | c.95 T > C | Leu32Pro | MS | / | / | / | [18, 25] | ||||||
| In 1 | c.194-3514delG | n.d. | Int | Ex 1α | c.106delG | Ala36Argfs*17 | PT | / | / | [15] | |||||||
| In 1 | c.194-3489_194-3488insAA | n.d. | Int | Ex 1α | c.131_132insAA | Tyr44* | PT | / | [56–58] | ||||||||
| In 1 | c.194-3488C > G | n.d. | Int | Ex 1α | c.132C > G | Tyr44* | PT | / | [56–58] | ||||||||
| In 1 | c.194-3488del | n.d. | Int | Ex 1α | c.132del | Tyr44* | PT | / | / | [59] | |||||||
| In 1 | c.194-3478C > A | n.d. | Int | Ex 1α | c.142C > A | Pro48Thr | MS | / | [25] | ||||||||
| In 1 | c.194-3477C > T | n.d. | Int | Ex 1α | c.143C > T | Pro48Leu | MS | / | [60] | ||||||||
| In 1 | c.194-3474 T > G | n.d. | Int | Ex 1α | c.146 T > G | Ile49Ser | MS | / | / | / | [18, 25] | ||||||
| In 1 | c.194-3472C > T | n.d. | Int | Ex 1α | c.148C > T | Gln50* c | PT | / | / | [32] | |||||||
| In 1 | c.194-3471A > C | n.d. | Int | Ex 1α | c.149A > C | Gln50Pro | MS | / | [52] | ||||||||
| In 1 | c.194-69C > T | n.d. | Int | In 1 | c.151-69C > T | – | Int | / (Uvl) | [61] | ||||||||
| In 1 | c.194-2A > G | n.d. | Splice | In 1 | c.151-2A > G | n.d. | Splice | / | [18] | ||||||||
| In 1 | c.194-1G > C | n.d. | Splicea | In 1 | c.151-1G > C | n.d. | Splicea | / | / | / | / | Osteochondroma | [11, 13, 62] | ||||
| Ex 2 | c.202G > C | Asp68His | MS | Ex 2 | c.159G > C | Met53Ile | MS | / | [32, 34] | ||||||||
| Ex 2 | c.202G > A | Asp68Asn | MS | Ex 2 | c.159G > A | Met53Ile | MS | / | / | [32] | |||||||
| Ex 2 | c.210G > T | Gln70His | MS | Ex 2 | c.167G > T | Ser56Ile | MS | / | [34, 35, 48, 63–65] | ||||||||
| Ex 2 | c.215C > T | Pro72Leu | MS | Ex 2 | c.172C > T | Arg58* d | PT | / | [25] | ||||||||
| Ex 2 | c.219 T > G | Ser73Arg | MS | Ex 2 | c.176 T > G | Val59Gly | MS | / | [4, 30, 33, 48, 64, 66–68] | ||||||||
| Ex 2 | c.237 T > C | Ala79= | Silent | Ex 2 | c.194 T > C | Leu65Pro | MS | / | [18, 25] | ||||||||
| Ex 2 | c.245_246delinsTT | Arg82Leu | MS | Ex 2 | c.202_203delinsTT | Ala68Leu | MS | / | / | [25] | |||||||
| Ex 2 | c.255A > G | Gln85= | Silent | Ex 2 | c.212A > G | Asn71Ser | MS | / | [4, 59, 69, 70] | ||||||||
| Ex 2 | c.256C > A | Leu86Met | MS | Ex 2 | c.213C > A | Asn71Lys | MS | / | / | / | Multiple myeloma | [17, 25] | |||||
| Ex 2 | c.262C > T | Arg88* | PT | Ex 2 | c.219C > T | Ala73= | Silent | Stomach ca. | [26] | ||||||||
| Ex 2 | c.268_286del / c.269_287del | Arg90Valfs*76 | PT | Ex 2 | c.225_243del / c.226_244del | Ala76Cysfs*64 e | PT | / | / | / | Uterine carcinomasarcoma | [18, 25, 32, 44, 71–76] | |||||
| Ex 2 | c.283_296del | Thr95Leufs*61 | PT | Ex 2 | c.240_253del | Pro81Cysfs*34 | PT | / | / | / | Papillary thyroid ca., uterine tumors | [77] | |||||
| Ex 2 | c.302C > T | Pro101Leu | MS | Ex 2 | c.259C > T | Arg87Trp | MS | / | [33, 55, 63, 78, 79] | ||||||||
| Ex 2 | c.303G > C | Pro101= | Silent | Ex 2 | c.260G > C | Arg87Pro | MS | / | / | / | [10, 25, 69, 80] | ||||||
| Ex 2 | c.305G > T | Gly102Val | MS | Ex 2 | c.262G > T | Glu88* | PT | / | [33, 81] | ||||||||
| Ex 2 | c.326del | Gly109Valfs*63 | PT | Ex 2 | c.283del | Val95Trpfs*51 | PT | / | [46] | ||||||||
| Ex 2 | c.451_454dupGGTG | Ala152Glyfs*51 | PT | Ex 2 | c.285_288dupGGTG | Leu97Glyfs*24 | PT | / | Low grade neuroepithelial tumor | [53] | |||||||
| Ex 2 | c.339G > C | Pro113= | Silent | Ex 2 | c.296G > C | Arg99Pro | MS | / | / | [25] | |||||||
| Ex 2 | c.344G > T | Arg115Leu | MS | Ex 2 | c.301G > T | Gly101Trp | MS | / | / | [18, 25, 32, 33, 67] | |||||||
| Ex 2 | c.350_351del | Ala117Glyfs*43 | PT | Ex 2 | c.307_308del | Arg103Alafs*16 | PT | / | [25, 34] | ||||||||
| Ex 2 | c.365G > T | Arg122Leu | MS | Ex 2 | c.322G > T | Asp108Tyr | MS | / | [82] | ||||||||
| Ex 2 | c.377C > G | Pro126Arg | MS | Ex 2 | c.334C > G | Arg112Gly | MS | / | [25] | ||||||||
| Ex 2 | c.378_380dup | Ser127dup | In-frame INS | Ex 2 | c.335_337dup | Arg112dup f | In-frame INS | / | / | / | non-Hodgkin’s lymphoma, cervical ca., phyllodes tumor | [10, 25] | |||||
| Ex 2 | c.382_383delinsCT | Ala128Leu | MS | Ex 2 | c.339_340delinsCT | Pro114Ser | MS | / | [63] | ||||||||
| Ex 2 | c.383_398del | Ala128Glufs*39 | PT | Ex 2 | c.340_355del | Pro114Argfs*27 | PT | / | [83] | ||||||||
| Ex 2 | c.*2del | – | 3’UTR | Ex 2 | c.358del | Glu120Serfs*26 | PT | / | / | / | [25, 67] | ||||||
| Ex 2 | c.*21 T > A | – | 3’UTR | Ex 2 | c.377 T > A | Val126Asp | MS | / | / | [4, 9, 32, 48, 69, 76] | |||||||
| Ex 2 | c.*23G > C | – | 3’UTR | Ex 2 | c.379G > C | Ala127Pro | MS | / | / | [52, 55, 84, 85] | |||||||
| Ex 2 | c.*101G > T | – | 3’UTR | Ex 2 | c.457G > T | Asp153Tyr | MS | / | / | [32] | |||||||
| In 2 | c.*102-105A > G | n.d. | 3’UTR | In 2 | c.458-105A > G | n.d. | Int | / | [25] | ||||||||
| Del part of Exon 2 | n.d. | PT | Del of Exon 1 & part of Exon 2 | / | [86] | ||||||||||||
| Del of entire CDS | – | Del of entire CDS | / | / | / | / | GBM, astrocytoma, meningioma | [12, 16] | |||||||||
Ex exon, In intron, CDS coding sequence, Del deletion, PT protein truncating, MS missense, INS in-frame insertion, Int intronic, 3UTR 3-prime UTR, ca. cancer, Mel melanoma, PCa pancreatic cancer, NST neural system tumors, Sarc sarcoma, BrCa breast cancer, HNSCC head and neck squamous cell carcinoma, LCa Lung cancer, NFB neurofibroma, Uvl uveal melanoma, NHL non-Hodgkin’s lymphoma, GBM glioblastoma multiforme, n.d. not determined
a Splice site alteration is experimentally shown to result in protein truncation through exon skipping
b Alternative names for NM_000077:c.-16_8dup (p.Ala4_Pro11dup) in the literature: 1_24dup, 23ins24, 32ins24, c.9_32dup24, c.24_47dup24, c.32_33ins24, c.32_33ins9_32, 24 bp duplication/insertion, p.M1_S8dup, p.1_8dup8
c Alternative name for NM_000077: c.148C > T (p.Gln50*) in the literature: 50Q > X
d Alternative name for NM_000077: c.172C > T (p.Arg58*) in the literature: p16INK4a Arg50Ter
e Alternative name for NM_000077: c.225_243del (p.Ala76Cysfs*64) in the literature: p16-Leiden
f Alternative names for NM_000077: c.335_337dup (p. Arg112dup) in the literature: 337-338insGTC, 113insR, 113insArg, p.R112_L113insR, 112-113insArg, p.Arg105ins