. These measure the significance of mutation burden,
                    clustering, and functional impact, respectively [&hellip;].
                    MutSigCV determines the P value for observing the
                    given quantity of non-silent mutations in the gene,
                    given the background model determined by silent (and
                    noncoding) mutations in the same gene and the
                    neighbouring genes of covariate space that form its
                    'bagel'. [&hellip;] MutSigCL and MutSigFN measure the
                    significance of the positional clustering of the
                    mutations observed, as well as the significance of the
                    tendency for mutations to occur at positions that are
                    highly evolutionarily conserved (using conservation as
                    a proxy for probably functional impact). MutSigCL and
                    MutSigFN are permutation-based methods and their P
                    values are calculated as follows: The observed
                    nonsilent coding mutations in the gene are permuted T
                    times (to simulate the null hypothesis, T = 108 for
                    the most significant genes), randomly reassigning
                    their positions, but preserving their mutational
                    'category', as determined by local sequence context.
                    We [use] the following context categories: transitions
                    at CpG dinucleotides, transitions at other C-G base
                    pairs, transversions at C-G base pairs, mutations at
                    A-T base pairs, and indels. Indels are unconstrained
                    in terms of where they can move to in the
                    permutations. For each of the random permutations, two
                    scores are calculated: SCL and SFN, measuring the
                    amount of clustering and function impact (measured by
                    conservation) respectively. SCL is defined to be the
                    fraction of mutations occurring in hotspots. A hotspot
                    is defined as a 3-base-pair region of the gene
                    containing many mutations: at least 2, and at least 2%
                    of the total mutations. SFN is defined to be the mean
                    of the base-pair-level conservation values for the
                    position of each non-silent mutation [&hellip;]. To determine
                    a PCL, the P value for the observed degree of
                    positional clustering, the observed value of SCL
                    (computed for the mutations actually observed), [is]
                    compared to the distribution of SCL obtained from the
                    random permutations, and the P value [is] defined to
                    be the fraction of random permutations in which SCL
                    [is] at least as large as the observed SCL. The P
                    value for the conservation of the mutated positions,
                    PFN, [is] computed analogously."