Variant classification summary

NM_033360.3:c.250A>G

KRAS · NP_203524.1:p.(Ile84Val) · NM_033360.3

GRCh37: chr12:25380208 T>C · GRCh38: chr12:25227274 T>C

Gene: KRAS Transcript: NM_033360.3

Final call

VUS

BP4 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.3

Protein

NP_203524.1:p.(Ile84Val)

gnomAD AF

6.196424167541396e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): REVEL 0.294 meets the VCEP pre-assigned <=0.3 threshold for missense variants.

2

Overall classification: VUS - only BP4 (Supporting) is applied, so no VCEP combination rule for Pathogenic, Likely Pathogenic, Benign, or Likely Benign is satisfied.

Final determination: Under the ClinGen RASopathy VCEP KRAS v2.3 criteria-combination framework, no combination rule matches the adjudicated criteria (only BP4 at Supporting strength is met; Rule19 requires >=2 benign Supporting criteria and no benign Strong, BA1, or pathogenic-direction criteria are met), so the variant remains a Variant of Uncertain Significance.

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: RASopathy disease mechanism is gain-of-function, and this missense change is not a null variant (no nonsense, frameshift, or splice-site consequence).	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PS2	Not assessed	Not assessed: no confirmed de novo observation (no parental testing or confirmation), so zero points under the VCEP de novo rule.	cspec clinvar PMID:28492532
PS3	Not assessed	Not assessed: no VCEP-approved functional assay result (RAS/MEK/ERK activation) exists for this exact variant.	cspec oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:28492532
PS4	Not assessed	Not assessed: no case-control or proband-cohort enrichment data exists; the single gnomAD allele (AF 6.2e-07) provides no enrichment signal.	cspec clinvar gnomad_v4 PMID:28492532
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM2	Not met	Not met: the variant is present in gnomAD v4.1 as a single South Asian exome allele (AF 6.2e-07), failing the VCEP absent-from-controls requirement. Flagged for human review: the lone allele may be a sequencing artifact (absent in gnomAD v2.1), in which case PM2 would be met.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	N/A	Not applicable: KRAS RASopathy is autosomal dominant with a gain-of-function mechanism, so the recessive trans-observation rule does not apply.	cspec
PM4	Not met	Not met: the change is missense (p.Ile84Val) with no protein length change - the 189-amino-acid protein is unchanged.	cspec spliceai
PM5	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM6	Not assessed	Not assessed: no de novo occurrence is reported with or without parental confirmation, so the VCEP point rule cannot be scored.	cspec clinvar PMID:28492532
PP1	Not assessed	Not assessed: no segregation data - zero informative meioses versus the >=3 required for Supporting.	cspec clinvar PMID:28492532
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PP3	Not met	Not met: REVEL 0.294 versus the VCEP >=0.7 threshold for missense variants.	revel spliceai bayesdel cspec
PP4	N/A	Not applicable: the RASopathy phenotype is broad and shared across RAS-MAPK genes, so gene-specific phenotype evidence is not credited.	cspec
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic/Likely pathogenic classification exists - only two laboratory VUS submissions (GeneDx, Labcorp).	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 AF 6.2e-07 (0.00006%) versus the >=0.05% BA1 threshold - roughly 800x below.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: gnomAD v4.1 AF 6.2e-07 versus the >=0.025% BS1 threshold - roughly 400x below.	gnomad_v4 gnomad_v2 cspec
BS2	Not met	Not met: no homozygous carriers in any population database; the single heterozygous carrier is not healthy-adult BS2 evidence.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS3	N/A	Not applicable: the RASopathy VCEP excludes benign functional-study evidence (BS3); no such assay is defined for this framework.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected individual tested and found not to carry the variant - not even one non-segregation meiosis exists.	cspec clinvar PMID:28492532
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP2	Not assessed	Not assessed: no proband or family observations exist (no phase, co-occurrence, or carrier data), so zero VCEP points can be scored.	cspec clinvar
BP3	N/A	Not applicable: no known benign repetitive regions in RASopathy genes, and the change is missense, not an in-frame indel.	cspec
BP4	Met	Met (Supporting): REVEL 0.294 meets the VCEP pre-assigned <=0.3 BP4 threshold for missense variants.	revel cspec spliceai bayesdel
BP5	Not assessed	Not assessed: no case-level evidence of an alternate molecular basis for disease in a carrier of this variant.	cspec clinvar
BP6	Not met	Not met: no ClinVar expert-panel Benign/Likely benign classification exists - only two laboratory VUS submissions.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous, intronic, or non-coding variants; this is a missense change (p.Ile84Val).	cspec

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