Variant classification summary

NM_033360.2:c.57G>T

KRAS · NP_203524.1:p.(Leu19Phe) · NM_033360.2

GRCh37: chr12:25398262 C>A · GRCh38: chr12:25245328 C>A

Gene: KRAS Transcript: NM_033360.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.2

Protein

NP_203524.1:p.(Leu19Phe)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

2

PP3 (Supporting): REVEL 0.797 exceeds the VCEP's >=0.7 missense threshold.

3

VUS: with only PM2 and PP3 at supporting strength, no KRAS VCEP combination rule is satisfied.

Final determination: No ClinGen RASopathy VCEP KRAS v2.3 criteria-combination rule (Rule1-Rule17) is satisfied by PM2 Supporting + PP3 Supporting alone, so the variant defaults to Uncertain Significance under the VCEP framework.

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: this is a missense substitution, and the KRAS VCEP marks PVS1 as not applicable to non-null variants.	cspec
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical p.Leu19Phe amino-acid change is documented.	pm5_candidates cspec
PS2	Not assessed	Not assessed: the only reported occurrence is somatic in colorectal tumors, with no germline proband or parental testing to establish a de novo event.	cspec PMID:17150185
PS3	Not assessed	Not assessed: no VCEP-approved functional assay result (e.g., RAS-GTP loading, MEK/ERK activation) exists for this variant.
PS4	Not assessed	Not assessed: no germline RASopathy case-control or phenotype data exist; only somatic colorectal-tumor cases were reported.	cspec PMID:17150185
PM1	Not met	Not met: codon 19 falls outside the VCEP's critical functional domains (P-loop AA 10-17, Switch I, Switch II, SAK).	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, as required by the KRAS VCEP.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is a recessive-disorder criterion, and the KRAS VCEP framework is autosomal-dominant.	cspec
PM4	N/A	Not applicable: this missense substitution causes no protein-length change, so the in-frame indel/stop-loss criterion does not apply.	cspec
PM5	Not assessed	Not assessed: no established pathogenic amino-acid substitution at codon 19 is documented in the available evidence.	pm5_candidates cspec
PM6	Not assessed	Not assessed: no presumed de novo germline occurrence without parental testing is documented; only a somatic tumor report exists.	cspec PMID:17150185
PP1	Not assessed	Not assessed: no familial segregation data are available; the only report is a somatic tumor study.	cspec PMID:17150185
PP2	N/A	Not applicable: the KRAS VCEP explicitly marks PP2 as not applicable for this gene.	cspec
PP3	Met	Met (Supporting): REVEL 0.797 exceeds the VCEP's >=0.7 missense threshold.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP designates PP4 as not applicable, directing phenotype assessment to PS4.	cspec
PP5	Not met	Not met: no ClinVar expert-panel classification exists; the only laboratory submission is zero-star and ineligible.	clinvar cspec
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.05% benign threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.025% threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy adult carriers of this variant are documented, so carrier phenotype and penetrance are unknown.
BS3	N/A	Not applicable: the KRAS VCEP explicitly marks BS3 as not applicable for this gene.	cspec
BS4	Not assessed	Not assessed: no informative meiosis shows the variant not segregating with disease; only somatic tumor data exist.	cspec PMID:17150185
BP1	N/A	Not applicable: the KRAS VCEP restricts BP1 to truncating variants, and this is a missense substitution.	cspec
BP2	Not assessed	Not assessed: no alternative molecular cause of a RASopathy in KRAS is documented.	cspec
BP3	N/A	Not applicable: the KRAS VCEP marks BP3 as not applicable, and this missense causes no protein-length change.	cspec
BP4	Not met	Not met: REVEL 0.797 is well above the VCEP's BP4 threshold of <=0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative molecular cause in another gene or RASopathy phenotype data are available.	cspec
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists for this variant.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies to synonymous or non-coding variants, and this is a missense substitution.	cspec

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