The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

Trubicka, Joanna; Żemojtel, Tomasz; Hecht, Jochen; Falana, Katarzyna; Piekutowska- Abramczuk, Dorota; Płoski, Rafał; Perek-Polnik, Marta; Drogosiewicz, Monika; Grajkowska, Wiesława; Ciara, Elżbieta; Moszczyńska, Elżbieta; Dembowska-Bagińska, Bożenna; Perek, Danuta; Chrzanowska, Krystyna H.; Krajewska-Walasek, Małgorzata; Łastowska, Maria

doi:10.1186/s12885-017-3211-y

Table 2 Germline candidate variants detected in the current study in DNA repair genes in medulloblastoma patients

From: The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

Variant	Gene	Effect on gene function	Wild type nucleotide	Altered nucleotide	Frequency in matched control group	Frequency in 1000 Genomes Database	Frequency in ExAC Database	“In silico” analysis of pathogenicity^a				High conserved nucleotide	Protein domain	ClinVar
Variant	Gene	Effect on gene function	Wild type nucleotide	Altered nucleotide	Frequency in matched control group	Frequency in 1000 Genomes Database	Frequency in ExAC Database	PolyPhen-2	SIFT	FATHMM	Mutation Taster	High conserved nucleotide	Protein domain	ClinVar
Missense, nonsense mutation and deletion
p.V606I	MSH2	missense	G	A	0	0	0	P score 0.868	T score 0.09	D score − 2.61	D score 0.9999	yes phyloP: 0.91	1.DNA mismatch repair protein MutS, 2.DNA mismatch repair protein MSH2	no data
p.A733T	MSH2	missense	G	A	0	0	0.000005	D score 0.985	D score 0	D score − 2.3	D score 0.9999	yes phyloP: 0.91	1.DNA mismatch repair protein MutS 2.P-loop containing nucleotide triphosphate hydrolase 3.DNA mismatch repair protein MSH2	no data
p.I171V	NBN	missense	A	G	0	0.001	0.00013	D score 1.000	D score 0	T score 1	D score 0.9999	yes phyloP: 0.96	1.BRCT domain 2.nibrin	RCV000007360.2 RCV000007361.2 RCV000115797.5
p.L219Afs	NBN	deletion	ACAAA	0	0	0	0.000019	-	-	-	D score 0.9999	-	1.nibrin	RCV000133576.3 RCV000007353.2
p.R695C	ERCC2	missense	G	A	0	0	0.000000012	D score 0.995	D score 0	D score − 3.00	D score 0.9999	yes phyloP: 0.91	1.Helicase C terminal domain	RCV000120773.1
p.R1093*	RAD50	stopgain	C	T	0	0	0.000001	-	-	-	D score 0.9999	yes phyloP: 0.84	1.DNA repair prtoien Rad50 2.P-loop containing nucleoside triphosphate hydrolase	RCV000006230.1
p.L694*	FANCM	stopgain	T	G	0	0	0	-	-	-	D score 0.9999	yes phyloP: 0.99	1.ERCC4, restriction endonuclease type II-like,	no data
Splice site mutation
								Human Splicing Finder	MaxEntScan	Splice Site Finder-like	Mutation Taster
p.V738L	EXO1	splice site	G	C	0	0	0.00000086	D score 93.10	D score 8.44	D score 91.77	D score 0.9999	yes phyloP: 0.89	-	no data

*Poly-Phen2: in the study, we used scores generated by the HumVar trained model as it is preferred for the diagnosis of Mendelian diseases. The scores range from 0 to 1, and a substitution with larger score has a higher possibility to damage the protein function. The program evaluates an amino acid substitution as D = probably damaging (if the score is in the range 1-0.909), P = possibly damaging (score is in the range 0.908-0.447), B = benign (score ≤ 0.446)
SIFT: SIFT The amino acid substitution is predicted to be D = damaging if the score is <0.05, otherwise it is predicted as T = tolerated
FATHMM: The amino acid substitution is predicted to be D = damaging if the score is < −1.5; otherwise SNP is predicted to be T = tolerated
MutationTaster: The scores range from 0 to 1. The larger score suggests a higher probability to cause a human disease. The program output is A = disease causing automatic, D = disease causing, N = polymorphism, P = polymorphism automatic

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ISSN: 1471-2407

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