Improved ACMG rule PM1

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:

• https://varsome.com/about/resources/acmg-implementation/