BAP1 genetic testing among melanoma and cancer-prone families in Sweden

Figures & data

Figure 1. Pathogenic variants identified in Sweden, plotted along the BRCA1-associated protein-1 (BAP1) gene with the functional domains shown. Ubiquitin carboxyl hydrolase (UCH) domain; HBM, host cell factor 1 (HCF1) binding domain; nuclear localization signals (NLS); C-terminal domain (CTD), additional sex combs like (ASXL1/2) binding domain; BRCA1-associated RING domain protein 1 (BARD1) binding region; Breast Cancer type 1 (BRCA1)-binding region and Ying Yang 1 (YY1) binding region; Forkhead Box Protein K1/2. ¹American College of Medical Genetics (ACMG) evidence: PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease. PM1-mutational hotspot, PM2–Absent from controls in Exome Aggregation Consortium (ExAC). PM4–Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants. PP1–Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP3–Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). PP4–Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. PS3–Functional studies. ²Functional studies of the missense variant c.281A > G, demonstrated an almost complete abolishment of enzymatic activity (Repo et al. Hum Mol Genet. 2019). This together with a co-segregation of a highly specific phenotype, absence of variant in controls, computational evidence and position in a hotspot gene site gives evidence that the variant is likely pathogenic.

Table 1. BAP1 germline genetic testing in 190 families from Sweden.

	Families tested for BAP1, N	Families with BAP1 PV, N
Type of family			%
Cutaneous melanoma families without other BAP1 core tumors^a	141	0	0.0%
Families with BAP1 core tumors^b	49	8	16.3%
Cutaneous melanoma (CM) in family	37	7	18.9%
Uveal melanoma (UM) in family	30	5	16.7%
BAP1-inactivated melanocytic tumor (BIMT) in family	9	7	77.8%
Renal cell cancer (RCC) in family	15	2	13.3%
Mesothelioma in family	6	5	83.3%
Meningioma in family	4	2	50.0%
Families with both:
CM and UM in family	20	4	20.0%
CM and RCC in family	15	2	13.3%
BIMT and CM in family	7	6	85.7%
BIMT and UM in family	4	4	100.0%
BIMT and mesothelioma in family	4	4	100.0%
UM and mesothelioma in family	3	3	100.0%

^aBAP1 core tumors (beside cutaneous melanoma); UM: uveal melanoma; RCC: mesothelioma, renal cell cancer; BIMT: meningioma, BAP1 inactivated melanocytic tumor.

^bFamilies with BAP1 core tumors had among probands and the first- and second-degree relatives:

CM in combination with other BAP1 core tumor(s),

BIMT in combination with other BAP1 core tumor(s),

UM in combination with other BAP1 core tumor(s), and

Two or more cases of UM.

Table 2. Tumors in BAP1 pathogenic variant carrying families identified in Sweden.

Family nr: cDNA change (protein change)	Cutaneous melanoma	Uveal melanoma	BIMT	Meso- thelioma	Meningioma	Renal cell cancer	Basal cell carcinoma	Other tumors (age at diagnosis), tumor-related death^†
S-138: c.58_59insTG, p(Glu20Valfs*53)
Number of individuals with diagnosis in family, n	1	1	1	0	1	0	2	Thymus (56 y), Bladder (60 y), Lung^† (70 y), Sarcomatous tumor^† (66 y)
Youngest age at diagnoses, years	53y	38y	11y	–	40y	–	54y
Tumor-associated deaths, n	0	0	0	–	0	–	0
S-442: c.58_59insTG, p(Glu20Valfs*53)
Number of individuals with diagnosis in family, n	0	1	2	1	0	0	0	Breast (56 y), Hypophysis (45 y), Pancreatic^† (67 y)
Youngest age at diagnoses, years	–	40y	51y	52y	–	–	–
Tumor-associated deaths, n	–	0	0	1	–	–	–
S-446: c.58_59insTG, p(Glu20Valfs*53)
Number of individuals with diagnosis in family, n	1	0	1	1	0	0	2	Pancreatic^† (49 y)
Youngest age at diagnoses, years	35y	–	32y	50y	–	–	39y
Tumor-associated deaths, n	0	–	0	1	–	–	0
S-163: c.79insG, p.(Val27fs)
Number of individuals with diagnosis in family, n	1	3	2	0	0	0	4	Prostate (67 y), Parotis (55 y), Lymphoma (62 y)
Youngest age at diagnoses, years	56y	16y	27y	–	–	–	50y
Tumor-associated deaths, n	0	3	0	–	–	–	0
S-164: c.281A > G, p.(His94Arg)
Number of individuals with diagnosis in family, n	2	2	0	2	0	0	2
Youngest age at diagnoses, years	Unknown	34y	–	60y	–	–	54y
Tumor-associated deaths, n	1	1	0	2	–	–	0
S-403: c.669C > A, p.(Tyr223*)
Number of individuals with diagnosis in family, n	1	0	1	0	1	0	1	Breast (44 y), Bile duct adenoma (72 y), Prostate (74 y)
Youngest age at diagnoses, years	45y	–	10y	–	61y	–	76y
Tumor-associated deaths, n	0	–	0	–	0	–	0
S-162: c.680_687delins13, p.(Arg227Profs*6)
Number of individuals with diagnosis in family, n	2	0	3	1 (in situ)	0	1	3	Lung cancer (77 y), Cutaneous squamous cell cancer (74 y)
Youngest age at diagnoses, years	44y	–	11y	39y	–	66y	49å
Tumor-associated deaths, n	0	–	0	0	–	1	0
S- 600: c.680_687delins13, p.(Arg227Profs*6)
Number of individuals with diagnosis in family, n	4	1	2	2	0	2	0	Breast (56 y)
Youngest age at diagnoses, years	20y	75y	10y	54y	–	69y	–
Tumor-associated deaths, n	0	0	0	2	–	1	–

^†Death from the tumor. 

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.