Variant classification summary

NM_006908.5:c.85C>T

RAC1 · NP_008839.2:p.(Pro29Ser) · NM_006908.5

GRCh37: chr7:6426892 C>T · GRCh38: chr7:6387261 C>T

Gene: RAC1 Transcript: NM_006908.5

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

RAC1

Transcript

NM_006908.5

Protein

NP_008839.2:p.(Pro29Ser)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: variant-specific biochemical, cellular, and in vivo studies show RAC1 p.Pro29Ser activation and oncogenic effects.

2

PM2 supporting: RAC1 c.85C>T is absent from the reported gnomAD datasets.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong criterion plus one supporting criterion does not meet a pathogenic or likely pathogenic combination, and no benign rule is satisfied, resulting in VUS.

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 met	Not met: RAC1 p.Pro29Ser is recurrently oncogenic in somatic melanoma, but no previously established pathogenic germline variant is documented.	PMID:22842228 PMID:23284172 PMID:25056119 clinvar
PS2	Not met	Not met: no de novo germline occurrence with confirmed parentage exists, and RAC1 P29S was somatic in every matched tumour-normal sample and absent from 2,577 germline exomes.	clinvar PMID:22842228 PMID:25056119
PS3	Met	Met, strong: independent biochemical, cellular, and in vivo assays consistently show RAC1 p.Pro29Ser activation, including significantly increased GDP-to-GTP exchange and enhanced tumor growth or drug resistance.	PMID:22842228 PMID:23284172 PMID:25056119 PMID:25465943
PS4	Not met	Not met: melanoma cohorts report RAC1 P29S in 7/147 tumors and 20/217 sun-exposed tumors, but these somatic frequencies do not establish germline PS4 case-control enrichment.	PMID:22842228 PMID:25056119 PMID:25465943
PM1	Not met	Not met: P29 lies in RAC1 switch I, but generic PM1 lacks established no-benign-variation evidence and the somatic hotspot route is unavailable without a VCEP rule.	PMID:22842228 PMID:25056119 hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from all reported gnomAD datasets, giving observed frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or parent/offspring phase testing establishes this variant in trans with a pathogenic allele.
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 met	Not met: no different missense change at RAC1 Pro29 is documented as pathogenic in the supplied ClinVar or literature evidence.	clinvar pm5_candidates PMID:22842228 PMID:23284172 PMID:25056119
PM6	Not met	Not met: no assumed de novo occurrence is reported, and the variant has never been detected in germline, including across more than 2,500 germline exomes.	clinvar PMID:22842228 PMID:25056119
PP1	Not assessed	Not assessed: no pedigree or affected relatives were ascertained, so co-segregation in multiple affected family members cannot be examined.
PP2	Not assessed	Not assessed: target-variant absence is available, but no gene-level benign-missense rate and missense-disease-mechanism evidence are supplied.	gnomad_v2 gnomad_v4
PP3	Not met	Not met: missense REVEL 0.585 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not met	Not met: no patient phenotype or family history is supplied that is highly specific for a disease with a single genetic etiology.	PMID:22842228 PMID:25056119 PMID:25465943
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification, and OncoKB's somatic Oncogenic label is not sufficient for PP5.	clinvar oncokb
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no filtering allele frequency reaching the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult carrier, homozygote, or hemizygote observation is documented for this variant.
BS3	Not met	Not met: no well-established benign functional or splicing result was identified, while multiple controlled assays consistently showed RAC1 p.Pro29Ser activation and oncogenic effects.	PMID:22842228 PMID:23284172 PMID:25056119 PMID:25465943
BS4	Not assessed	Not assessed: no family with affected members was ascertained, so lack of segregation among affected relatives cannot be demonstrated.
BP1	Not assessed	Not assessed: no gene-level disease spectrum shows that RAC1-related disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no clinical phase data show this variant in trans or cis with a pathogenic variant under the BP2 definition.
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 0.585 is above the generic BP4 supporting threshold of 0.29.	revel
BP5	Not met	Not met: the evidence documents somatic melanoma observations but no clinical case showing this variant alongside an alternate molecular basis for the evaluated disease.	PMID:22842228 PMID:25056119
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification, and no qualifying independent benign assertion is present.	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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