Hereditary Cancer in Clinical Practice

Table 5 In silico analysis of the MLH1, MSH2 and MSH6 variants

From: Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

Gene	Coding variants	In silico predictions
Gene	Coding variants	AlignGVGD	PolyPhen2	SIFT	MutPred	SNPs&GO	PhD-SNP	SNAP	Consensus^a
MLH1	c.1913G > T (G638 L)	C15	Probably damaging	Deleterious	Benign	Neutral	Neutral	Neutral	B (3/7)
MLH1	c.1919C > T (P640L)	C65	Probably damaging	Deleterious	Deleterious	Disease	Disease	Disease	LP (7/7)
MSH2	c.944G > T (G315 V)	C0	Benign	Deleterious	Benign	Neutral	Neutral	Neutral	B (1/7)
	c.1074G > C (E358D)	C35	Possibly damaging	Tolerated	Benign	Neutral	Disease	Neutral	B (3/7)
	c.2120G > A (C707Y)	C0	Probably damaging	Damaging	Benign	Disease	Disease	Disease	LP (5/7)
MSH6	c.3151G > A (V1051I)	C0	Benign	Tolerated	Benign	Neutral	Neutral	Neutral	B (0/7)
Noncoding variants		Splice-site predictions
Noncoding variants		SpliceSiteFinder-like		MaxEntScan	NNSPLICE	GeneSplicer	HumanSpliceSite Finder		Consensus^{b, c}
MLH1	c.116 + 3A > T	D (75.7 → 0)		D (8.6 → 2.4)	D (0.9 → 0)	D (5.5 → 0)	NE		LP (4/5)
	c.116 + 4C > A	NE		NE	NE	NE	NE		B (0/5)
	c.1990-26 T > C	NE		NE	NE	NE	NE		B (0/5)
MSH2	c.2006-36_2006-33dup	NE		NE	NE	NE	NE		B (0/5)
MSH6	c.457 + 50 T > A	NE		NE	NE	NE	NE		B (0/5)
	c.3556 + 170del	NE		NE	NE	NE	NE		B (0/5)
	c.4001 + 26A > G	NE		D (0 → 2.9)	NE	NE	D (0 → 71.4)		B (2/5)

B Benign, D Donor, LP Likely pathogenic, NE No effect
^aThe variant is considered as likely pathogenic by five of the seven protein function prediction algorithms
^b The variant is considered as likely pathogenic by four of the five splice-site prediction algorithms
^c > 20% change in score (i.e., a wild-type splice-site score decreases and/or a cryptic splice-site score increases) is considered as significant

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