Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach

Table 2 SIFT PROVEAN analysis outcome of the two variants of prime interest identified in the 11 family members

HUGO gene symbol	Chromosome	HGVS description of variant	HGMD tag	Aminoacid position	Reference residue	Alternative residue	Variation type	PROVEAN prediction		SIFT prediction
HUGO gene symbol	Chromosome	HGVS description of variant	HGMD tag	Aminoacid position	Reference residue	Alternative residue	Variation type	Score	Prediction	Score	Prediction
MSH2	2	c.2732T>A	NA	911	L	Q	Single AA Change	−4.14	Deleterious	0.001	Damaging
BRCA1	17	c.2955delC	DM	986			Frameshift	NA	NA	NA	NA

Source: PROVEAN v1.1.3 (PROVEAN human genome variants tool, http://provean.jcvi.org/genome_submit_2.php?species=human).PROVEAN was developed in order to predict whether a given protein sequence variation (single or multiple amino acid substitutions, micro-insertions, micro-deletions) affects protein function. To achieve this, PROVEAN introduces a delta alignment score based on the reference and variant versions of a protein query sequence with respect to sequence homologs (NCBI NR protein database through BLAST, http://www.ncbi.nlm.nih.gov/). The default score threshold was set at −2.5 for binary classification (deleterious<−2.5 vs. neutral>−2.5). Similarly (through PSI-BLAST, http://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Web&PAGE=Proteins&PROGRAM=blastp&RUN_PSIBLAST=on), SIFT (http://sift.jcvi.org/) may be applied to naturally occurring non-synonymous polymorphisms. SIFT score ranges from 0 to 1. A SIFT score of ≤0.05 corresponds to a “damaging” prediction, whereas a SIFT score >0.05 predicts that the variant is likely to be “tolerated”
NA not available (where the precomputed score was not available in the database, the precomputed homologous protein identifiers for the query protein were retrieved in order to bypass the BLAST search and clustering, and the score was computed based on the homologs)

ISSN: 1479-7364