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Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in-silico approach that applies ACMG/AMP curation in an automated manner using the tool for assessment and prioritization in exome studies (TAPES), which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in or