LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_018890.4_c.85C_T_20261105_121758
Framework: ACMG/AMP 2015
Variant classification summary

NM_018890.4:c.85C>T

RAC1  · NP_061485.1:p.(Pro29Ser)  · NM_018890.4
GRCh37: chr7:6426892 C>T  ·  GRCh38: chr7:6387261 C>T
Gene: RAC1 Transcript: NM_018890.4
Final call
Pathogenic
PS3 strong PS4 strong PM1 moderate PM2 supporting BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAC1
Transcript
NM_018890.4
Protein
NP_061485.1:p.(Pro29Ser)
gnomAD AF
ClinVar
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong functional assays demonstrated RAC1 P29S gain of function.
2
Pathogenic: PS4 strong melanoma enrichment had corrected odds ratios above 5 with confidence intervals excluding 1.
3
Pathogenic: PM1 moderate supports a statistically significant recurrent RAC1 P29 hotspot without observed benign variation.
4
Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.
5
BP5 supporting does not satisfy a benign rule on its own and therefore does not create conflicting evidence.
Final determination: Under the generic ACMG/AMP 2015 framework, two Strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; BP5 Supporting alone does not satisfy a benign rule.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no independently established pathogenic alternate-nucleotide p.Pro29Ser comparator was identified, and ClinVar retrieval failed.
clinvar PMID:22842228 PMID:23284172 PMID:25056119
PS2 Not assessed Not assessed: no affected proband, confirmed maternity and paternity, and absent family history are documented for this RAC1 variant.
PS3 Met Met, strong: independent biochemical, cellular, and mouse-xenograft assays consistently demonstrated RAC1 P29S gain of function versus wild type.
PMID:23284172 PMID:22842228 PMID:25056119 PMID:25465943
PS4 Met Met: melanoma case-control comparisons gave corrected ORs 275.18 and 539.02, both >5.0 with 95% confidence intervals excluding 1.0.
PMID:22842228 PMID:25465943
PM1 Met Met at moderate strength: P29S is a statistically significant recurrent hotspot, reported in 4%–9% of melanomas and absent from gnomAD v2.1 and v4.1.
hotspots gnomad_v2 gnomad_v4 PMID:22842228 PMID:25056119 PMID:25465943
PM2 Met Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, below the PM2 threshold of <=0.0001.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no parental or offspring genotypes establish a pathogenic variant in trans or a recessive inheritance mode for RAC1-associated disease.
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no different missense substitution at RAC1 Pro29 was established as pathogenic in the available evidence.
pm5_candidates clinvar PMID:22842228 PMID:23284172 PMID:25056119
PM6 Not assessed Not assessed: no affected proband or parental testing results establish an assumed de novo RAC1 c.85C>T occurrence.
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or familial co-segregation data are reported for RAC1 c.85C>T.
PP2 Not assessed Not assessed: no supplied gene-level evidence establishes both low benign missense variation and a common disease-causing missense mechanism for RAC1.
PP3 Not met Not met: missense REVEL score 0.585 is below the >=0.644 PP3 supporting threshold.
revel
PP4 Not assessed Not assessed: no patient phenotype or family history is available to evaluate highly specific disease features.
PP5 Not assessed Not assessed: ClinVar lookup failed, so no exact-variant expert-panel Pathogenic or Likely pathogenic classification is available.
clinvar
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, so no grpmax FAF reached the BA1 threshold of >=0.05.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, with no grpmax FAF reaching the generic BS1 threshold of >=0.01.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no healthy adult carrying the variant was documented, and no genotype-level evidence supports the BS2 healthy-adult requirement.
BS3 Not assessed Not assessed: reviewed studies show RAC1 P29S activation, but no validated assay demonstrates no damaging effect on protein function or splicing.
PMID:23284172 PMID:22842228 PMID:25056119 PMID:25465943
BS4 Not assessed Not assessed: no affected relatives with documented absence of RAC1 c.85C>T provide evidence of lack of segregation.
BP1 Not assessed Not assessed: the available evidence does not show that RAC1 disease is primarily caused by truncating variants.
BP2 Not assessed Not assessed: no phase data show the variant in cis or trans with a pathogenic variant, and a fully penetrant dominant RAC1 disorder is not established.
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL score 0.585 exceeds the <=0.29 BP4 supporting threshold.
revel
BP5 Met Met: all three RAC1 P29S cases in a 45-patient cohort also had BRAF V600-mutant melanoma, providing an alternate molecular basis.
PMID:25056119
BP6 Not assessed Not assessed: ClinVar lookup failed, so no exact-variant expert-panel Benign or Likely benign classification is available.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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