RUNX1 c.393T>C, p.(Phe131=)

Rule

RUNX1 MM-VCEP PM2_Supporting: minor allele frequency <=0.00005 with at least 2000 alleles tested and adequate coverage; when grpmax FAF is unavailable, all subpopulations should meet threshold.

Evidence considered

• gnomAD v2.1 absent
• gnomAD v4.1 total AF 6.195372304703279e-07
• Highest observed subpopulation AF 1.666222340709144e-05 in AMR

Still missing

• No grpmax FAF value was available in gnomAD v4.1
• so threshold assessment relies on the observed subpopulation frequencies.

Sources

Rule

RUNX1 MM-VCEP BP4 for synonymous and intronic variants requires SpliceAI <=0.20.

Evidence considered

• SpliceAI max delta score 0.07
• RUNX1 pilot results include synonymous variants curated with BP4/BP7 as benign-supporting evidence patterns.

Sources

Rule

RUNX1 MM-VCEP BP7 applies to synonymous variants outside the specified splice-edge positions when SpliceAI <=0.20.

Evidence considered

• Exon 2 spans c.271-c.427
• c.393 is internal to the exon.
• SpliceAI max delta score 0.07
• RUNX1 pilot results include synonymous variants curated with BP7.

Sources

Rule

RUNX1 MM-VCEP PVS1 applies through the modified RUNX1 PVS1 decision tree for qualifying loss-of-function or splice-disrupting variants.

Evidence considered

• RUNX1 is eligible for PVS1 in the MM-VCEP framework.
• The variant is a synonymous substitution.
• SpliceAI max delta score is 0.07.

Still missing

• No RNA or minigene study was identified to evaluate a noncanonical splicing effect.

Sources

Rule

PS1/PS1_Moderate requires the same amino acid change as an established pathogenic or likely pathogenic variant; splice-site PS1 follows SVI splicing recommendations.

Evidence considered

• ClinVar lists this variant as a synonymous change with expert panel review but does not provide a same-effect pathogenic comparator.

Still missing

• No same-effect pathogenic or likely pathogenic comparator variant was identified.

Sources

Rule

RUNX1 MM-VCEP PM1 applies to protein-altering variants affecting specified residues in the RHD, with stronger weighting for 13 defined hotspot residues.

Evidence considered

• Cancer Hotspots did not show this variant in a statistically significant hotspot.
• RUNX1 PM1 is specified for protein-altering variants in defined residues/region.

Sources

Rule

RUNX1 MM-VCEP PM4 applies to qualifying in-frame indels in the RHD or stop-loss variants causing protein extension.

Evidence considered

• Variant consequence is synonymous.

Sources

Rule

RUNX1 MM-VCEP PM5 applies to qualifying missense variants, or to certain downstream truncating variants, under stated caveats.

Evidence considered

• Variant consequence is synonymous.

Sources

Rule

RUNX1 MM-VCEP PP3 for synonymous or intronic variants requires SpliceAI >=0.38.

Evidence considered

• SpliceAI max delta score 0.07

Sources

Rule

RUNX1 MM-VCEP BA1 requires MAF >=0.0015 in a general continental population dataset with >=2000 alleles tested and >=5 variant alleles.

Evidence considered

• Highest observed subpopulation AF 1.666222340709144e-05 in AMR

Sources

Rule

RUNX1 MM-VCEP BS1 requires MAF between 0.00015 and 0.0015 in a qualifying general continental population dataset with >=2000 alleles tested and >=5 variant alleles.

Evidence considered

• Highest observed subpopulation AF 1.666222340709144e-05 in AMR

Sources

Rule

RUNX1 MM-VCEP PS2_Supporting requires 1 proven de novo occurrence and PS2_Moderate requires >=2 proven de novo occurrences in an FPD/AML phenotype.

Evidence considered

• RUNX1 MM-VCEP requires one confirmed de novo occurrence for PS2_Supporting and at least two for PS2_Moderate.

Still missing

• No case report or submitter data documenting confirmed de novo status were identified.

Sources

Rule

RUNX1 MM-VCEP PS3 requires abnormal transactivation and/or qualifying secondary functional assay evidence.

Evidence considered

• OncoKB did not provide variant-specific functional evidence.

Still missing

• No variant-specific functional or RNA study was identified.

Sources

Rule

RUNX1 MM-VCEP PS4 requires >=1 phenotype-qualified proband for PS4_Supporting, 2-3 for PS4_Moderate, or >=4 for PS4.

Evidence considered

• ClinVar reports expert panel review but does not provide the proband count needed for PS4.

Still missing

• No verified proband count meeting RUNX1 phenotype criteria was identified.

Sources

Rule

RUNX1 MM-VCEP PM6_Supporting requires 2-3 assumed de novo occurrences and PM6 requires >=4 assumed de novo occurrences in an FPD/AML phenotype.

Evidence considered

• RUNX1 MM-VCEP requires 2-3 assumed de novo occurrences for PM6_Supporting and >=4 for PM6.

Still missing

• No case report or submitter data documenting assumed de novo status were identified.

Sources

Rule

RUNX1 MM-VCEP PP1 requires 3-4 informative meioses for supporting, 5-6 for moderate, and >=7 for strong evidence.

Evidence considered

• RUNX1 MM-VCEP PP1 requires 3 or more informative meioses.

Still missing

• No pedigree or meiosis count was identified.

Sources

Rule

RUNX1 MM-VCEP BS3 requires normal function in qualified assays, with stronger evidence when normal transactivation is supported by a secondary assay.

Evidence considered

• No variant-specific benign functional evidence was retrieved.

Still missing

• No variant-specific RNA
• minigene
• or other benign functional study was identified.

Sources

Rule

RUNX1 MM-VCEP BS4 is applicable when a variant is observed to not segregate in >=2 informative meioses.

Evidence considered

• RUNX1 MM-VCEP BS4 requires >=2 informative meioses.

Still missing

• No informative meioses showing lack of segregation were identified.

Sources

Rule

RUNX1 MM-VCEP BP2 follows the ACMG/AMP co-occurrence framework.

Evidence considered

• No co-occurrence evidence was retrieved.

Still missing

• No phase or homozygosity data were identified.

Sources