Rule PM1 now only considers missense & in-frame variants when evaluating a hot-spot. This significantly reduces false-positives, though it does have a small impact on sensitivity too.
For example: variant BRCA1:Lys503Arg would previously trigger PM1, when in fact there are no pathogenic missense variants in this area, although there are many null variants:
If we filter the above for missense variants we obtain:
With thanks to Roberto Doliana Ph.D, National Cancer Institute, CRO-IRCCS, Italy, for bringing this issue to our attention.
Check out the complete VarSome's ACMG documentation for more details:
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