Table 2.
Rare variants of interest in ATM candidate gene.
| Case Index (Age of Diagnosis) | Gene 1 | Description and Consequence | Type | ACMG Classification 2 | DbSNP 3 | gnomAD 4 | CADD 5 | SIFT 6 | Polyphen 7 | LRT 8 | Mutation Taster | Other Cancer in Family | Clin Var 9 | Co-Segregation 10 | Total No. of cm/um Cases in Family |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CM (24) | ATM | c.1516G>T:p.(Gly506Cys) | missense | VUS | rs587779816 | 29.0 | D | P | D | D | ON, PC | UNC | ND | 1 CM | |
| CM (48) | ATM | c.1595G>A:p.(Cys532Tyr) | missense | VUS | rs35963548 | 21.0 | D | D | D | D | 2 CM, BC | UNC | ND | 3 CM | |
| CM (47) | ATM | c.3275C>A;p.(Ser1092Ter) | non sense | P | - | - | - | - | - | D | D | PC, LC | - | ND | 1 CM |
| MPM (42, 42) | ATM | c.3576G>A;p.(Ser1135_Lys1195del58) | splicing | LP | rs587776551 | 1.63e-05 | - | - | - | - | - | CM | P | ND | 3 CM |
| CM (49) | ATM | c.3576G>A;p.(Ser1135_Lys1195del58) | splicing | LP | rs587776551 | 1.63e-05 | - | - | - | - | - | CM, UC | P | ND | 2 CM |
| MPM (40, 40) | ATM | c.3576G>A;p.(Ser1135_Lys1195del58) | splicing | LP | rs587776551 | 1.63e-05 | - | - | - | - | - | MPM, BCC, PC, PR | P | Y | 4 CM |
| MPM (35, 63) | ATM | c.3934A>G:p.(Arg1312Gly) | missense | VUS | rs864622137 | 23.3 | D | D | D | D | LC, BR, GC | UNC | ND | 2 CM | |
| CM (45) | ATM | c.4049C>T:p.(Thr1350Met) | missense | VUS | rs587781785 | 27.0 | T | D | D | D | CM | UNC | ND | 3 CM | |
| CM (50) | ATM | c.4306C>T:p.(His1436Tyr) | missense | VUS | rs544891616 | 17.09 | T | D | D | D | 2 KD | UNC | ND | 1 CM | |
| HL (35), MPM (45, 45, 46), BCC (49), PC (50) | ATM | c.4451delT:p.(Met1484ArgfsTer15) | frameshift | P | - | - | - | - | - | - | CM, CC, LC, PC | - | ND | 4 CM | |
| CM (47) | ATM | c.5750G>C:p.(Arg1917Thr) | missense | LP | rs377289524 | 1.22e-05 | 25.6 | T | D | D | D | CM, UM, BC, BLC, PR, CC, GC | UNC | Y | 2 CM, 1 UM |
| MPM (45, 46) | ATM | c.5750G>C:p.(Arg1917Thr) | missense | LP | rs377289524 | 1.22e-05 | 25.6 | T | D | D | D | PR | UNC | ND | 2 CM |
| 2 UM (41), CM (51) | ATM | c.5979_5983delTAAAG; p.(Ser1993ArgfsTer23) | frameshift | P | rs876660134 | 8.13e-06 | - | - | - | - | - | BC, GC, LX | P | ND | 1 CM, 2 UM |
| MPM (48, 48, 53), BCC (49) | ATM | c.8319_8323dupTGTCC; p.(Pro2775LeufsTer33) | frameshift | P | rs1060501552 | - | - | - | - | - | MPM, BCC, PC, PR | P | ND | 5 CM | |
| CM (43) | ATM | c.8557A>G:p.(Thr2853Ala) | missense | VUS | - | 27.7 | D | D | D | D | MES | UNC | ND | 1 CM |
1 Gene reference: ATM LRG_135 (NM_000051.3). 2 ACMG: American College of Medical Genetics and Genomics; 3 dbSNP: single nucleotide polymorphism database; 4 gnomAD: genome aggregation database; 5 CADD: combined annotation-dependent depletion; 6 SIFT: sorting intolerant from tolerant; 7 PolyPhen: polymorphism phenotyping; 8 LRT: likelihood ratio test; 9 Clin Var (ClinVar aggregates information about genomic variation and its relationship to human health); 10 co-segregation analysis of variant with melanoma phenotype in the family (Y: the observed variant co-segregates in at least two affected members; ND: not done). Abbreviations; ATM: ataxia-telangiectasia mutated; BC: breast cancer; BCC: basal cell carcinoma; BLC: bladder cancer; CC: colon cancer; CM: cutaneous melanoma; D: deleterious; GC: gastric cancer; HL: Hodgkin lymphoma; LX: larinx cancer; LP: likely pathogenic; MES: malignant mesothelioma; MPM: multiple primary melanoma; ON: pncocytoma; P: pathogenic; PC: pancreatic cancer; PR: prostate cancer; T: tolerant; UC: uterine cancer; UM: uveal melanoma; UNC: uncertain; VUS: variant of unknown significance. The variants in bold are novel.