Table 1:
HDR (non-functional score) of BRCA2 missense DBD variants and ACMG framework classification.
| Variant (p.) | HDR Score | ACMG codes | Classification | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||
| PM1 | PM5 | PP1 | PM3/BP2 | PP3/BP4 (PROVEAN) | BA1/BS1/PM2 (Frequency) | BP5 | PP_Multifac/BP_Multifac | PS3/BS3 | pre-HDR | post-HDR | ||
|
| ||||||||||||
| p.His2623Arg | 0.83 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published* | LPATH | LPATH |
| p.Leu2686Pro | 0.86 | PM1 | - | - | PM3 | BP4 | PM2 | - | - | PS3 | LPATH | PATH |
| p.Leu3101Pro | 0.90 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Leu2653Pro | 0.92 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published* | PATH | PATH |
| p.Asp2723His | 1.00 | PM1 | PM5 | - | - | BP4 | PM2 | - | PP_Multifac | PS3-published* | PATH | PATH |
| p.Gly2748Asp | 0.95 | PM1 | - | - | - | BP4 | PM2 | - | PP_Multifac _Strong | PS3-published* | PATH | PATH |
| p.Arg3052Trp | 0.97 | PM1 | - | - | - | BP4 | PM2 | - | PP_Multifac _Strong | PS3-published* | PATH | PATH |
| p.Asp2723Val | 0.98 | PM1 | PM5 | - | - | PP3 | PM2 | - | - | PS3 | LPATH | PATH |
| p.Asn3124Ile | 0.99 | PM1 | - | - | - | PP3 | PM2 | - | PP_Multifac | PS3-published* | PATH | PATH |
| p.Gly2748Ser | 0.97 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Val3072Glu | 0.97 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Leu2647Pro | 1.00 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Leu2604Pro | 0.98 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Asp2723Ala | 0.99 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Ala2730Pro | 1.01 | PM1 | - | - | - | BP4 | - | - | - | PS3 | VUS | LPATH |
| p.Gly3076Glu | 1.04 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Tyr3006Asp | 1.06 | PM1 | - | - | - | PP3 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Asn3124Lys | 1.06 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Trp2788Arg | 1.05 | PM1 | - | - | - | PP3 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Phe3146Ser | 1.06 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Gly2609Val | 1.08 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Ser2691Phe | 1.10 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Trp2626Arg | 1.09 | PM1 | - | - | - | PP3 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Leu2510Pro | 1.06 | PM1 | - | - | PM3 | BP4 | PM2 | - | - | PS3 | LPATH | PATH |
| p.Thr2722Arg | 1.08 | PM1 | PM5 | - | - | BP4 | PM2 | - | PP_Multifac | PS3-published^ | PATH | PATH |
| p.Phe2562Val | 1.08 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Gly2724Trp | 1.12 | PM1 | - | - | PM3 | BP4 | PM2 | - | - | PS3 | LPATH | PATH |
| p.Glu3002Lys | 1.10 | PM1 | - | PP1_Moderate | - | BP4 | PM2 | - | - | PS3-published* | PATH | PATH |
| p.Val2687Phe | 1.14 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Gly2596Glu | 1.12 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Leu3101Arg | 1.15 | PM1 | - | - | PM3_Strong | BP4 | PM2 | - | - | PS3 | LPATH | PATH |
| p.Tyr2660Asp | 1.17 | PM1 | - | PP1 | - | PP3 | PM2 | - | - | PS3-published* | PATH | PATH |
| p.Val2652Gly | 1.14 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.His2623Tyr | 1.15 | PM1 | PM5 | - | - | BP4 | PM2 | - | - | PS3 | LPATH | LPATH |
| p.Arg2625Ile | 1.17 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Gly2793Arg | 1.18 | PM1 | - | - | - | PP3 | PM2 | - | PP_ Multifac | PS3-published^ | PATH | PATH |
| p.Ala3028Pro | 1.18 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Gly2585Arg | 1.24 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Leu2654Pro | 1.31 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Phe2562Cys | 1.32 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Tyr2726Cys | 1.36 | PM1 | - | - | - | PP3 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Arg2784Trp | 1.35 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3-published^ | LPATH | LPATH |
| p.Arg2824Thr | 1.36 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
| p.Thr2722Ala | 1.39 | PM1 | - | - | - | BP4 | PM2 | - | - | PS3 | VUS | LPATH |
PM1-protein structure; PM5-pathogenic effect for alteration of same residue; PM3-Fanconi anemia phenotype; BP2-healthy biallelic patients; PP1-cosegregation in family; BA1/BS1/PM2-Population Frequency Codes; BP5-Co-occurrence; BS3/PS3-published
: previous classification using BS3/PS3 evidence from HDR assays published by the Couch laboratory; BS3/PS3-published
: previously classified using BS3/PS3 evidence from functional studies by Couch and other laboratories (see Supplementary Table 2). Abbreviations: HDR-homology directed repair; CI-confidence interval; Multifac -Multi-factorial; LPATH-Likely Pathogenic; P-Pathogenic; LBEN-Likely Benign; BEN-Benign; VUS-Variant of Uncertain Significance.