Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

Mur, Pilar; De Voer, Richarda M.; Olivera-Salguero, Rubén; Rodríguez-Perales, Sandra; Pons, Tirso; Setién, Fernando; Aiza, Gemma; Valdés-Mas, Rafael; Bertini, Angelo; Pineda, Marta; Vreede, Lilian; Navarro, Matilde; Iglesias, Silvia; González, Sara; Brunet, Joan; Valencia, Alfonso; Esteller, Manel; Lázaro, Conxi; Kops, Geert J. P. L.; Urioste, Miguel; Puente, Xose S.; Capellá, Gabriel; Valle, Laura

doi:10.1186/s12943-018-0762-8

Molecular Cancer

Table 1 Germline genetic variants in BUB1 and BUB3 identified in 544 CRC and/or polyposis families

From: Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

^aMutation [protein domain]	BUB1 c.1965-1G>A (r.1965_1975del; p.S655Rfs*32)	BUB1 c.2296G>A (p.E766K)	BUB1 c.2473C>T (p.P825S) [Kinase domain]	BUB3 c.77C>T (p.T26I) [WD40 repeat 1]
Population MAF (%) (1000G / ESP / ExAC/ gnomAD)	n.r.	n.r.	rs748392521; n.r. / n.r. / 0.004 / 0.005	n.r.
Protein function prediction (score)	p.S655Rfs*32	^bPPH2: PsD (0.934) / N (0.349)	^bPPH2: PrD (1 / 0.997)	^bPPH2: PsD (0.770 / 0.548)
		SIFT: N (0.2)	SIFT: D (< 0.0001)	SIFT: N (0.06)
		Condel: N (0.463)	Condel: D (0.542)	Condel: D (0.524)
		Mut. Taster: D	Mut. Taster: D	Mut. Taster: D
		Align GVGD: N (C0)	Align GVGD: D (C65)	Align GVGD: N (C0)
Protein stability prediction (ddG, Kcal/mol)	p.S655Rfs*32	CUPSAT: destabilizing (−0.69)	CUPSAT: destabilizing (−1.16)	CUPSAT: destabilizing (− 0.29)
		ERIS: destabilizing (1.57)	ERIS: stabilizing (−0.71)	ERIS: destabilizing (1.10)
		I-Mutant: destabilizing (−0.53)	I-Mutant: destabilizing (−0.64)	I-Mutant: destabilizing (− 0.68)
		PoPMuSIC: destabilizing (0.04)	PoPMuSIC: stabilizing (0.17)	PoPMuSIC: destabilizing (0.33)
Splice site predictions (Alamut v2.9)	Disrupts acceptor site	No change	No change	No change
Splice site predictions (Alamut v2.9)	RNA study: 11 bp deletion	RNA study: no change	No change	RNA study: no change
^cEvolutionary conservation (PhyloP / PhastCons)	–	1.239 / 0.95	4.358 / 1	5.572 / 1
Variegated aneuploidy	No	No	n.a.	No
Somatic LOH / promoter methylation	n.a. / n.a.	No LOH; No methylation (II.6 and III.2)	No LOH; No methylation	No LOH; n.a.
Functional studies in LCL	Damaging effects	No effect (incomplete functional assessment)	n.a.	n.a.
^d,eVariant classification	^ePathogenic	Likely benign / Uncertain significance	Uncertain significance	Uncertain significance

a. RefSeq GRCh37: BUB1 NM_004336, BUB3 NM_004725
b. Polyphen 2: HumDiv / HumVar scores.
c. PhyloP score (values between -14 and +6): Sites predicted to be conserved are assigned positive scores. PhastCons score (values between 0 and 1): the closer the value is to 1, the more probable the nucleotide is conserved.
d. According to the standard guidelines for the interpretation of sequence variants (recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology) [7].
e. Interpret with caution. BUB1 and BUB3 have not yet been defined as genes with clinical value in hereditary cancer.
Abbreviations: 1000G, 1000 Genomes; bp, base pairs; ca., cancer; D, damaging or deleterious; ESP, NHLBI GO Exome Sequencing Project; ExAC, Exome Aggregation Consortium; GnomAD, Genome Aggregation Database (http://gnomad.broadinstitute.org); LCL, EBV-transformed lymphoblastoid cell line; N, neutral; n.a., not available; n.r., not reported; PPH2, polyphen 2; PrD, probably damaging; PsD, possibly damaging

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ISSN: 1476-4598

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