Variant classification summary

NM_001369786.1:c.101C>T

KRAS · NP_001356715.1:p.(Pro34Leu) · NM_001369786.1

GRCh37: chr12:25398218 G>A · GRCh38: chr12:25245284 G>A

Gene: KRAS Transcript: NM_001369786.1

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

KRAS

Transcript

NM_001369786.1

Protein

NP_001356715.1:p.(Pro34Leu)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.101C>T (p.Pro34Leu, p.P34L) variant has been reported in ClinVar as pathogenic and has been reviewed by the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.

3

In published and VCEP-approved functional studies, this variant showed abnormal KRAS signaling behavior, including increased active GTP-bound KRAS and markedly reduced GAP-stimulated GTP hydrolysis with downstream pathway activation, consistent with a damaging gain-of-function effect.

4

Computational evidence supports a deleterious missense effect, with REVEL 0.867 above the KRAS RASopathy PP3 threshold of 0.7, BayesDel 0.425277 supportive of pathogenicity, and SpliceAI showing no meaningful splice disruption (maximum delta score 0.02).

Final determination: Rule14 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	This is a missense variant, and the KRAS RASopathy specification marks PVS1 as not applicable for this gene-disease framework.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No reviewed source identified a different nucleotide change that produces this same amino acid substitution and is independently established as pathogenic, so PS1 is not met.	cspec clinvar
PS2	Not assessed	No confirmed de novo observation with verified maternity and paternity was identified for this variant in the reviewed sources, so PS2 cannot be assigned from the available evidence.	cspec
PS3	Met	In approved KRAS functional assays, this variant showed abnormal signaling behavior consistent with a damaging gain-of-function effect. Published experiments reported increased active GTP-bound KRAS, marked reduction of GAP-stimulated GTP hydrolysis for P34L comparable to oncogenic G12V, and downstream pathway activation; the RASopathy VCEP functional-study file lists this variant as a pathogenic control in RAS activation, MEK activation, and ERK activation assays. This supports PS3 at Moderate strength because at least two different approved assays are available.	cspec PMID:20949621 vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	Although this variant has been reported in affected individuals and is classified as pathogenic in ClinVar, the reviewed sources did not provide a verified proband count or point total required for PS4 under the KRAS RASopathy specification.	cspec clinvar PMID:17056636
PM1	Met	This missense change affects codon 34, which lies within the KRAS Switch I domain. The KRAS RASopathy specification defines Switch I as amino acids 25-40, a critical and well-established functional domain for PM1, so PM1 is met at Moderate strength.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the KRAS RASopathy requirement that the variant be absent from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the KRAS RASopathy specification.	cspec
PM4	N/A	This is not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply.	cspec
PM5	Met	A different pathogenic missense change has been reported at this same codon. Specifically, KRAS p.Pro34Arg has been reported in an individual with cardio-facio-cutaneous syndrome and is discussed in subsequent functional literature, supporting PM5 at Moderate strength for this novel residue change at codon 34.	cspec PMID:16474405 PMID:17875937
PM6	Not assessed	No reviewed source provided sufficient evidence that this variant occurred de novo without confirmed maternity and paternity, so PM6 cannot be assigned from the available data.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 is not met from the available evidence.	cspec
PP2	N/A	PP2 is not applicable in this KRAS RASopathy framework.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. REVEL is 0.867, which is above the KRAS RASopathy PP3 threshold of 0.7; BayesDel is 0.425277, also supporting a damaging effect; and SpliceAI predicts no meaningful splice disruption with a maximum delta score of 0.02, indicating the concern is the missense change rather than altered splicing. This meets PP3 at Supporting strength.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in the KRAS RASopathy specification.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of 0.05%, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025%, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations in unaffected individuals were identified, so BS2 cannot be assessed from the available evidence.	cspec
BS3	N/A	BS3 is not applicable in this KRAS RASopathy framework.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.	cspec
BP1	N/A	BP1 in this framework is reserved for truncating loss-of-function variants in genes without established loss-of-function disease correlation, and this variant is missense.	cspec
BP2	Not assessed	No evidence was identified that this variant was observed with another pathogenic variant in a context relevant to the KRAS RASopathy BP2 point framework.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy specification.	cspec
BP4	Not met	Computational evidence does not support a benign effect. REVEL is 0.867, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.425277; SpliceAI predicts little splice impact with a maximum delta score of 0.02, but the missense-prediction evidence overall does not support BP4.	cspec revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis or clearly inconsistent phenotype was identified, so BP5 cannot be assessed from the available evidence.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is not a synonymous or noncoding variant, so BP7 does not apply.	cspec

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