Reasoning
Under the ENIGMA BRCA1/2 v1.2 specification, PP1 is applicable only as a quantitative co-segregation likelihood ratio (PP1 Supporting LR >= 2.08:1, Moderate >= 4.3:1, Strong >= 18.7:1, Very Strong >= 350:1; LR between 0.48 and 2.08 provides no supporting evidence in either direction). The ENIGMA multifactorial dataset (Parsons et al. 2019, HUMU-40-1557-s001 SuppT1) contains an exact-match row for BRCA2 c.10111A>G p.(Thr3371Ala), but its Segregation LR cell is blank, meaning no co-segregation data contributed to the model; the non-blank Co-occurrence LR (1.51) and Family History LR (7.10) components are clinical-history/co-occurrence evidence (PP4/BP5 domain), not segregation. No retrieved publication reports segregation of this variant in affected relatives. With no segregation LR or informative meioses available, PP1 cannot be scored (neither met nor refuted), so it is returned not_assessed pending segregation data.
Rule
ENIGMA BRCA1/2 v1.2 PP1: co-segregation in multiple affected family members measured by quantitative co-segregation analysis; PP1 Supporting LR >=2.08:1, Moderate LR >=4.3:1, Strong LR >=18.7:1, Very Strong LR >=350:1 (Appendix I).
Evidence considered
- ENIGMA BRCA1/2 v1.2 CSPEC PP1 rule: 'Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method' with Bayes-score weights PP1 LR >=2.08:1 (Supporting), >=4.3:1 (Moderate), >=18.7:1 (Strong), >=350:1 (Very Strong); instructions add that LR >0.48 and <2.08 provides no supporting evidence in either direction.
- Parsons et al. 2019 multifactorial likelihood table (vcep_humu_40_1557_s001, SuppT1, exact variant match) lists BRCA2 c.10111A>G p.(Thr3371Ala) with a blank Segregation LR cell; only Co-occurrence LR 1.51 and Family History LR 7.10 contribute to the combined LR, i.e., the multifactorial model contains no segregation component for this variant.
- SuppT2 of the same source attributes the c.10111A>G data points to the Easton et al. 2007 dataset, but no cosegregation likelihood ratio for the variant is reported in any retrieved VCEP table or paper.
- PMID:27376475, the only retrieved publication that mentions c.10111A>G, reports the variant in a single heterozygous proband from an NGS validation cohort and contains no family segregation analysis.
Still missing
- No quantitative co-segregation LR for c.10111A>G is available: the Segregation LR cell is empty in Parsons et al. 2019 SuppT1 and no ENIGMA reference-set (Supplementary Table 7) row or publication reporting segregation in affected family members was found.
- Segregation analysis (number of affected carriers/non-carriers and meioses, computed via COOL or CAL-Leiden per ENIGMA Appendix I) would be required before PP1 can be applied.
Sources