Variant classification summary

NM_004985.4:c.178G>C

KRAS · NP_004976.2:p.(Gly60Arg) · NM_004985.4

GRCh37: chr12:25380280 C>G · GRCh38: chr12:25227346 C>G

Gene: KRAS Transcript: NM_004985.4

Final call

Likely Pathogenic

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

Variant details

Gene

KRAS

Transcript

NM_004985.4

Protein

NP_004976.2:p.(Gly60Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.178G>C (p.Gly60Arg) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar, where it is classified as Pathogenic including review by the ClinGen RASopathy expert panel.

2

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

3

In a published functional study, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK signaling relative to wild type, consistent with an activating effect; the RASopathy VCEP approved functional-study resource also supports use of multiple approved assay types for this variant.

4

Computational evidence supports a damaging missense effect, with REVEL 0.938 above the KRAS PP3 threshold of 0.7 and a positive BayesDel score of 0.539464; SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified.

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
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BA1 threshold of 0.05% and BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BP1	N/A	This is a missense variant, not a truncating variant, so the KRAS RASopathy BP1 rule for truncating variants in a gain-of-function disease context does not apply.	cspec
BP2	Not assessed	No phased second pathogenic variant in KRAS and no point-based evidence for an alternative molecular cause in the same gene were identified, so BP2 was not assessed.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy framework because there are no established benign repetitive regions for this rule in these genes.	cspec
BP4	Not met	Available computational evidence does not support a benign missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy BP4 benign threshold of 0.3, and BayesDel is also positive at 0.539464.	revel bayesdel cspec
BP5	Not assessed	No confirmed alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not used in this KRAS RASopathy framework.	cspec
BP7	N/A	This is a missense variant, not a synonymous or noncoding change, so BP7 does not apply.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BS1 threshold of 0.025% and BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No confirmed unaffected adult carriers or point-based BS2 evidence were identified, so BS2 was not assessed.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy framework, and the available functional studies support abnormal rather than normal KRAS activity.	cspec PMID:20949621
BS4	Not assessed	No informative non-segregation data were identified for this variant, so BS4 was not assessed.	cspec
PM1	Met	This missense variant affects KRAS residue 60, which lies within the Switch II region (amino acids 57-64), a critical and well-established functional domain specified for PM1 in the KRAS RASopathy framework.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the KRAS RASopathy PM2 requirement for absence from population controls.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the KRAS RASopathy framework.	cspec
PM4	N/A	This is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply.	cspec
PM5	Met	Different missense substitutions at KRAS codon 60 have been reported as pathogenic or likely pathogenic in ClinVar, including p.Gly60Val and p.Gly60Ser, which supports the classic same-residue PM5 rule at moderate strength for this novel amino acid change.	clinvar cspec
PM6	Not assessed	Affected-case reports were identified in the literature and ClinVar, but no directly verified assumed de novo occurrence suitable for PM6 point assignment was confirmed from the reviewed evidence.	clinvar PMID:19396835 PMID:20949621 cspec
PP1	Not assessed	No informative familial segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy framework.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy PP3 threshold of 0.7, and BayesDel is also positive at 0.539464. SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified to establish a splice-based mechanism.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in the KRAS RASopathy framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
PS1	Not met	No different nucleotide change producing the same amino acid substitution with established pathogenic classification was identified for KRAS p.Gly60Arg, so PS1 is not met.	clinvar cspec
PS2	Not assessed	Published affected-case evidence exists for this variant, but no directly confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was verified from the reviewed sources, so PS2 was not assessed.	clinvar PMID:19396835 PMID:20949621 cspec
PS3	Met	In published functional studies, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK phosphorylation relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study resource lists this variant as a pathogenic control in multiple approved assay types, which supports PS3 at moderate strength because two or more different approved assays were available.	PMID:20949621 vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been reported in affected individuals and is classified as pathogenic by the ClinGen RASopathy expert panel in ClinVar, but the reviewed evidence did not establish the point total required by the KRAS RASopathy PS4 framework, so PS4 was not assessed.	clinvar PMID:19396835 PMID:20949621 cspec
PVS1	N/A	This is a missense variant and does not fall into a null-variant category. The KRAS RASopathy framework lists PVS1 as not applicable for this case context, and the generic PVS1 scaffold also indicates that this variant is not a nonsense, frameshift, or canonical splice-site change.	cspec pvs1_variant_assessment

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