NM_004985.4:c.173C>T

KRAS · NP_004976.2:p.(Thr58Ile) · NM_004985.4

GRCh37: chr12:25380285 G>A · GRCh38: chr12:25227351 G>A

Gene: KRAS Transcript: NM_004985.4

Final call

VUS

PS3 moderate PM1 moderate PP3 supporting PP5 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.4

Protein

NP_004976.2:p.(Thr58Ile)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The KRAS c.173C>T (p.Thr58Ile, T58I) variant has been observed in somatic cancer literature and has also been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at 1/1613990 alleles (AF 6.19583e-07; 0.00006%), which is far below the KRAS RASopathy VCEP benign frequency thresholds.

In published functional studies, p.Thr58Ile showed defective intrinsic GTP hydrolysis, impaired responsiveness to GAP-mediated regulation, and abnormal downstream signaling; the RASopathy VCEP approved functional study set also includes this variant as a pathogenic or likely pathogenic control in multiple approved assay classes, supporting a gain-of-function effect.

Computational evidence supports a deleterious missense effect, with REVEL 0.921 above the VCEP PP3 threshold of 0.7, BayesDel 0.42458, and SpliceAI showing no significant splice effect (max delta score 0.03).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this variant does not fall into a null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified here showing the same amino acid change, p.(Thr58Ile), from a different nucleotide change that is already established as pathogenic.	cspec clinvar
PS2	Not assessed	Published literature reports de novo KRAS mutations including p.(Thr58Ile), but the available evidence reviewed here does not provide enough detail on parental confirmation and phenotype point assignment to apply the RASopathy VCEP de novo scoring rule confidently.	cspec PMID:16474405
PS3	Met	In VCEP-approved functional datasets, p.(Thr58Ile) appears as a pathogenic or likely pathogenic validation control in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. Published studies also showed defective intrinsic GTP hydrolysis, impaired GAP responsiveness, and deregulated downstream signaling, consistent with a gain-of-function effect.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:16474405 PMID:20949621
PS4	Not assessed	This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but the reviewed evidence does not provide enough case counting and point assignment detail to apply the RASopathy VCEP PS4 scoring framework.	cspec clinvar PMID:16474405 PMID:16921267 PMID:19396835
PM1	Met	The p.(Thr58Ile) change lies in the KRAS Switch II region, which the KRAS RASopathy VCEP defines as a critical and well-established functional domain spanning amino acids 57-64. Codon 58 falls within this curated domain.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	This variant is not absent from controls because it is present in gnomAD v4.1 at 1/1613990 alleles (AF 6.19583e-07; 0.00006%), although it is absent from gnomAD v2.1. Because the RASopathy VCEP PM2 rule requires absence from gnomAD, PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PM4	N/A	This variant is a missense substitution and does not create a protein length change such as an in-frame insertion or deletion or stop-loss event, so PM4 is not applicable.	cspec
PM5	Not assessed	No reviewed evidence here established a different pathogenic or likely pathogenic amino acid change at codon 58 that would allow PM5 to be applied.	cspec clinvar
PM6	Not assessed	Published literature suggests de novo occurrence of p.(Thr58Ile), but the reviewed evidence does not provide enough detail to assign a de novo point total under the RASopathy VCEP PM6 framework.	cspec PMID:16474405
PP1	Not assessed	No segregation data were identified to show cosegregation of this variant with disease in informative meioses.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. The REVEL score is 0.921, which is above the KRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.42458, and SpliceAI predicts no significant splice impact with a max delta score of 0.03, supporting a missense rather than splice-mediated mechanism.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	The observed population frequency does not reach the BA1 threshold. In gnomAD v4.1 the variant is present at 0.00006% (1/1613990 alleles), which is well below the KRAS RASopathy VCEP BA1 threshold of 0.05%.	cspec gnomad_v4
BS1	Not met	The observed population frequency does not reach the BS1 threshold. In gnomAD v4.1 the variant is present at 0.00006% (1/1613990 alleles), which is below the KRAS RASopathy VCEP BS1 threshold of 0.025%.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in the number of unaffected individuals required for the RASopathy VCEP BS2 point system.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant.	cspec
BP1	N/A	This rule is intended in this framework for truncating variants in a gain-of-function disease setting without established loss-of-function correlation. The current variant is a missense change, so BP1 is not applicable.	cspec
BP2	Not assessed	No phase data or alternative molecular explanation data were identified to support BP2 scoring.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy VCEP framework because no benign repetitive region rule is defined for this gene set.	cspec
BP4	Not met	Computational evidence does not support a benign effect. The REVEL score is 0.921, which is above the benign BP4 threshold of 0.3 for this VCEP.	cspec revel
BP5	Not assessed	No alternative molecular diagnosis or phenotype explanation was identified that would support BP5 scoring.	cspec
BP6	N/A	BP6 is not applicable in the KRAS RASopathy VCEP framework.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or relevant intronic change, so BP7 is not applicable.	cspec

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