Table 1 Overview of germline (likely) pathogenic variants and variants of unknown significance identified by exome-based cancer predisposition gene testing of individuals who developed multiple primary tumors.

From: Exome-based cancer predisposition gene testing can provide a genetic diagnosis for individuals with heterogeneous tumor phenotypes

Gene	Patient ID	Sex (F/M)	(Pre)malignancies (age)^a	Benign lesions and other clinical features (age)^a	Transcript ID	Genomic position (genome build hg19)	cDNA position	Protein change	Zygosity	SpliceAI score	ACMG classification	ACMG pathogenicity	Diagnostic analyses performed^b	Cohort^c	Study
CHEK2	UPN001	M	Dysplastic nevi skin (40); Mel (43); TC (49); Essential thrombocythemia (59); CRC (60); CLL (64); Bowen’s disease (66); PC (67); Skin (67)	Hemangioma skin (37); Nevi naevocellularis (37, 38, 44); BCC (43, 51, 66)*; Lipoma subcutis (53); Pol (64)	NM_007194.4	chr22: g.29091857del	c.1100del	p.(Thr367MetfsTer15)	hom	NA	PVS1; PM2; PS4	Pathogenic	MSH2, MSH6, WES panel hereditary cancer (DG-2.5)**	D	ref15^#
CHEK2	UPN008	F	TC (53); EC (53); CIS-AD (54); BC (54); UCC (62)	Pol (53, 54, 55, 57, 64, 64); Nevi naevocellularis (54)	NM_007194.4	chr22: g.29091857del	c.1100del	p.(Thr367MetfsTer15)	hom	NA	PVS1; PM2; PS4	Pathogenic	PTEN, WES panel hereditary cancer (DG-2.13)**	D	ref15^#
CHEK2	UPN009	M	CRC (64); CRC (64)	Lipoma (63); Trichilemmoma (39); Pol (64)	NM_007194.4	chr22: g.29091857del	c.1100del	p.(Thr367MetfsTer15)	hom	NA	PVS1; PM2; PS4	Pathogenic	PTEN	R	ref15^#
FANCM	UPN102	F	HnNC (40); OrC (40); EsC (49)	NR	NM_020937.4	chr14: g.45636336 C > T	c.1972C>T	p.(Arg658Ter)	hom	NA	PVS1; PM3; PM2; PS3	Pathogenic	WES panel hereditary cancer (DG-2.12)**	D	This study
NF1	UPN126	F	TC (48); DCIS (51); BC (51)	Thyroid nodules; Breast fibroadenomas; Multiple neurofibromas; Cafe-au lait spots	NM_001042492.3	chr17: g.29553697 C > G	c.2246 C > G	p.(Ser749Ter)	het	NA	PVS1; PM2; PS4	Pathogenic	PTEN, BRCA1, BRCA2, CHEK2 c.1100del	R	This study
POT1	UPN232	F	OvC (43); Mel (55, 72, 74); TC (60); Ly (60); LC (62); Sarcoma (79)	BCC (60)*	NM_015450.3	chr7: g.124510964 C > A	c.255+1 G > T	p.?	het	0.9762	PVS1; PM2; PS4	Pathogenic	BRCA1, BRCA2, WES panel hereditary cancer (DG-2.18)**	D	This study
PTEN	UPN133	F	BC (45); EC (46)	Atypical breast fibroadenoma (33); Bra (46); Pancreas tumor (47)	NM_000314.8	chr10: g.89690851 G > C	c.253+5 G > C	p.?	het	0.848	PP3; PM2; PS1	Likely pathogenic	PTEN^$, TP53, BRCA1, BRCA2	R	This study
HOXB13	UPN090	M	Mel (63); PC (64); LC (70)	NR	NM_006361.6	chr17: g.46805705 C > T	c.251 G > A	p.(Gly84Glu)	het	NA	PM2; PP1	Pathogenic	WES panel hereditary cancer (DG_2.4.1)**	D	This study
MAX	UPN078	M	PGC (31)	Adr (51); Acromegaly	NM_002382.5	chr14: g.65544706 T > C	c.220 A > G	p.(Met74Val)	het	NA	PM2; PP3; PM1; PP2	VUS	MAX, MEN1, WES panel hereditary cancer (DG-2.10)**	D	This study
RECQL4	UPN114	M	BlC (49); CRC (63)	Pol (63); Macrocephaly	NM_004260.4	chr8: g.145737770 C > T	c.3055+5 G > A	p.?	comp het	0.4039	PM2; PP3	VUS	APC, MUTYH, PTEN	R	This study
RECQL4	UPN114	M	BlC (49); CRC (63)	Pol (63); Macrocephaly	NM_004260.4	chr8: g.145739073 G > A	c.2082 C > T	p.(Gly694 = )	comp het	0.5161	PM2; PP3	VUS	APC, MUTYH, PTEN	R	This study

ACMG American College of Medical Genetics and Genomics, Adr adrenal gland tumor, BC breast cancer, BCC basal cell carcinoma, BlC bladder cancer, Bra brain tumor, cDNA complementary DNA, CIS-AD carcinoma in situ-adenoma, CLL chronic lymphocytic leukemia, com het compound heterozygous, CRC colorectal cancer, D diagnostics, DCIS ductal carcinoma in situ, DG version of a gene panel (internal Radboudumc label), EC endometrial cancer, EsC esophageal carcinoma, F female, het heterozygous, hg19 human genome build 19, HnN head and neck tumor, hom homozygous, LC lung cancer, Ly lymphoma, M male, Mel melanoma, NR not reported, OrC oropharyngeal carcinoma, OvC ovarian carcinoma, PC prostate cancer, PGC pituitary gland carcinoma, Pol colorectal polyp, R research, TC thyroid cancer, UCC urothelial carcinoma, VUS variant of uncertain significance, WES whole-exome sequencing.
*Counted as benign due to its benign behavior.
**WES panel hereditary cancer (DG_version) includes panel of genes associated with cancer development. This panel is regularly updated at Radboudumc. For specific versions of the gene panel see: https://www.radboudumc.nl/en/patient-care/patient-examinations/exome-sequencing-diagnostics/exomepanelspreviousversions/exomepanelspreviousversions/hereditary-cancer.
^#Cases and their UPN IDs are identical to Hinić et al., (2024).
^$The PTEN variant was previously during targeted gene testing not considered pathogenic at that time.
^aNumber in the brackets denotes the age at which a tumor/cancer was diagnosed.
^bReports all previous analyses in the diagnostic setting for the respective individual.
^cVariant was identified though WES in the diagnostic cohort (D) or research cohort (R).

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Table 1 Overview of germline (likely) pathogenic variants and variants of unknown significance identified by exome-based cancer predisposition gene testing of individuals who developed multiple primary tumors.

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