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Reference: Tavtigian S.V., Deffenbaugh A.M., Yin L., Judkins T., Scholl T., Samollow P.B., de Silva D., Zharkikh A., Thomas A. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet. (2006) 43 (4) 295-305.
Hosted: Hosted at The International Agency for Research on Cancer (IARC) – part of the World Health Organization (WHO). (http://agvgd.iarc.fr/index.php)

Summary: Align-GVGD uses a MSA to characterise the biochemical properties (composition, polarity and volume) of the observed amino acids at each position

Methodology:
• The biochemical variation at each alignment position is converted to a Grantham Variation score (GV).
• The difference between these properties and those of the variant amino acid being assessed are calculated and a Grantham Difference score generated (GD).
• These values are used as a measure of how likely the substitution is to be deleterious or neutral on a classification spectrum.

Input:
Align-GVGD requires an alignment. Predictions are found to be highly varied depending on the alignment used. Using highly divergent sequences in an alignment can introduce gaps and will result in all amino acids being classed as neutral at that position. In an attempt to overcome this, manually curated alignments are available to use which contain 8-14 orthologous sequences from a range of species. These alignments cover ATM, BRCA1, BRCA2, CHEK2, TP53, MLH1 and MSH1. For each of these gene alignments, the user must select the species depth of the alignment. For example for BRCA1, the alignment can span species from human to frog, human to pufferfish or human to sea urchin. The depth of the alignment will influence sequence diversity over the sites and thus effect the prediction.

Output:
The prediction classes form a spectrum (C0, C15, C25, C35, C45, C55, C65) with C65 most likely to interfere with function and C0 least likely.