Table 4.
Additional germline CDKN1B variants and somatic whole-exome sequencing findings
| MAF in gnomAD (%), P value (compared with our cohort) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| HGVS nomenclature: DNA, proteina | Location in gene, variant type | dbSNP ID | MAF in our cohort (%) | Findings in tumor samples (WES) | gnomAD exomes | gnomAD genomes | gnomAD exomes+ genomes | VarSome ACMG classification | Functional data and clinical associations |
| c.-386C>T, p.? | 5′ UTR, intronic. | rs886049078 | 0.2604 | n/a | n/a | 0.0287, P = .1145 | Likely benign. | ClinVar RCV000293046.1: MEN/VUS. | |
| c.-202C>T, p.? | 5′ UTR, intronic. | rs183710253 | 0.7813 | Heterozygous in 1/27 (same as germline). | n/a | 0.7172, P = .7575 | Likely benign. | ClinVar RCV000359300.1: MEN/likely benign. Polymorphism in (56). | |
| c.-126C>T, p.? | 5′ UTR, intronic. | rs549943001 | 0.2551 | n/a | n/a | 0.1179, P = .3761 | Likely benign. | ClinVar RCV000264729.1: MEN/likely benign. | |
| c.-79C>T, p.? | 5′ UTR, intronic. | rs34330 | 28.8265b | Heterozygous in 10/27 and homozygous in 16/27. LOH in one case. | n/a | 30.5275, P = .4673 | Benign. | Reduced transcriptional activity (57, 58). Association with increased risk of hereditary prostate cancer (33), breast cancer (59-61), lung cancer (62), follicular variant of papillary thyroid carcinoma (57), endometrial cancer (63), hepatocellular cancer (64), and neuroblastoma (58). Increased cancer susceptibility, especially in Asians, in a meta-analysis (65). HGMD (CR040861): disease-associated polymorphism with additional supporting functional evidence. | |
| c.24C>T, p.N8= | Exon 1, synonymous. | rs371308246 | 0.2551 | n/a | 0.0040, P = .0171 | 0.0033, P = .0245 | 0.0039, P = 0.0166 | Likely benign. | ClinVar RCV000542803.2: MEN4/ likely benign. |
| c.326T>G, p.V109G | Exon 1, missense. | rs2066827 | 23.2143 | Heterozygous in 10/27 and homozygous in 3/27 (same as germline). | 25.8753, P = .2293 | 36.0140, P < .0001 | 27.0108, P = .0907 | Benign. | Increased colony formation and cell growth rate when overexpressing this variant in AtT20 cells (66). Association with increased risk of squamous cell carcinoma of the head and neck (67), breast cancer progression (68, 69), endometriosis (70), ovarian cancer (71), corticotropinomas (66), papillary thyroid carcinoma (72), prostate cancer (73), and type 2 diabetes mellitus (74). No correlation with overall cancer risk in the general population in a meta-analysis (75). For medullary thyroid carcinoma, both increased risk (76) and association with favorable disease progression (77) have been reported. Reduced risk of prostate cancer (78), ovarian cancer (79), and melanoma (80). Increased risk of aggressive tumors in MEN1 patients (81). HGMD (CM033961): disease-associated polymorphism. ClinVar RCV000244836.2 and RCV000755233.1: not specified/benign, RCV000295040.1: MEN/benign, RCV000568315.1: hereditary cancer-predisposing syndrome/benign. |
| c.475 + 10C>T, p.? | Intron 1, intronic. | rs36101844 | 0.2551 | Heterozygous in 1/27 (same as germline). | 0.0149, P = .0581 | 0.0987, P = .3278 | 0.0247, P = .0937 | Likely benign. | ClinVar: RCV000476950.3: MEN4/benign, RCV000301956.1: MEN/likely benign. |
| c.475 + 49C>T, p.? | Intron 1, intronic. | rs201914302 | 0.2551 | n/a | 0.0099, P = .0397 | 0.0318, P = .1276 | 0.0128, P = .0505 | Likely benign. | COSMIC (COSN10100669): somatic change in one kidney cancer case. |
| c.475 + 105G>C, p.? | Intron 1, intronic. | rs994095606 | 0.2717c | n/a | n/a. | 0.0064, P = .0344 | VUS | n/a | |
| c.476-153T>G, p.? | Intron 1, intronic. | rs142894418 | 0.2717c | n/a | n/a. | 0.1179, P = .358 | Likely benign. | n/a | |
| c.476-77T>C, p.? | Intron 1, intronic. | rs3093731 | 0.8152c | n/a | n/a | 0.2803, P = .0892 | Likely benign. | n/a | |
| c.*9-64A>G, p.? | 3′ UTR, intronic. | rs76967889 | 0.2604 | n/a | n/a | 0.0892, P = .2973 | Likely benign. | n/a | |
| c.*9-38C>T, p.? | 3′ UTR, intronic. | rs4251695 | 0.2604 | n/a | n/a | 0.2706, P>09999 | Likely benign. | n/a | |
| c.*181T>C, p.? | 3′ UTR, intronic. | rs4251696 | 0.2604 | n/a | 0.2769, P>.9999 | 1.0542, P = .1978 | 0.3731, P>.9999 | Likely benign. | ClinVar RCV000333902.1: MEN/benign. |
| c.*452C>T, p.? | 3′ UTR, intronic. | rs762469235 | 0.2577 | n/a | n/a | 0.0127, P = .0596 | Likely benign. | ClinVar RCV000290740.1: MEN/VUS. | |
| c.*956C>A, p.? | 3′ UTR, intronic. | rs7330 | 45.0000d | n/a | n/a | 57.4794, P = .2676 | Benign. | ClinVar RCV000396437.1: MEN/benign. | |
ACMG, American College of Medical Genetics and Genomics; LOH, loss of heterozygosity; MAF, minor allele frequency; MEN, multiple endocrine neoplasia; UTR, untranslated region; VUS, variant of uncertain significance; WES, whole-exome sequencing.
aAll variants were annotated according to the reference sequences NCBI GenBank NM_004064.4 and UniProt P46527-1.
bT is reported as the wild type nucleotide, but it is the minor allele; therefore, frequencies and associations are presented for the T allele.
c Only covered in whole-exome sequencing samples.
dOnly covered in Sanger-sequenced samples.