Pathogenicity calculation rules for cases beyond ACMG 2015

[kgliu0101]

Since modified values were added to criteria, there are cases not covered in ACMG Guidelines 2015, e.g. case 2 PVS (very strong) and case 2 BA (stand alone). Right now, such cases result assertion "Uncertain significance - insufficient evidence".

Below are calculated results of case 1 PVS + 1 PS (strong) and case 2 PVS.

It's probably necessary to clarify how to calculate such cases.

[kgliu0101]

@selinad and @wrightmw Please review this issue when you get time.

[selinad]

HI @kgliu0101 good catch re 2 x PVS and 2 x BA. We will check for you I would think 2 x PVS would result in a Pathogenic.

[selinad]

@kgliu0101 - I just communicated with Steven. I'm not sure how difficult this is, so let me know at this late date.

He said that PS2 is really the only criterion so far that people bump to a VS. Is it possible to alter it so that's the case? If so, the following would hold:

PVS1 + PS2_Very_strong is Pathogenic PS2_Very_strong + any S = Pathogenic

Let me know if this makes sense....thx!

[kgliu0101]

@selinad What about case 2 BA? Same as 1 BA with assertion Benign?

[selinad]

Hi @kgliu0101 - I didn't ask on that one. Since you are already at Benign with 1 BA, I think 2 would have to be benign. I guess the real question is whether there are any other Benign criteria that could get to BA1. They can report back to us about this upon testing.

[selinad]

@kgliu0101 - were you going to change it so only PS2 has possibility of switching to PVS, based on the above - for the UI pull-downs? I'm sorry if there was confusion over this...

[kgliu0101]

@selinad Yes, in ticket #910.

[selinad]

This appears to have been sorted out in #910 -- closing