Variant classification summary

NM_001369787.1:c.508A>T

KRAS · NP_001356716.1:p.(Met170Leu) · NM_001369787.1

GRCh37: chr12:25362788 T>A · GRCh38: chr12:25209854 T>A

Gene: KRAS Transcript: NM_001369787.1

Final call

VUS

BP4 supporting

Variant details

Gene

KRAS

Transcript

NM_001369787.1

Protein

NP_001356716.1:p.(Met170Leu)

gnomAD AF

6.2054911149778215e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.508A>T (p.Met170Leu) variant has been reported in ClinVar and is classified there as uncertain significance, including an expert-panel submission from the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (10/1,611,476 alleles; AF 0.00062%), which is below the KRAS BA1 threshold of 0.05% and the BS1 threshold of 0.025%.

3

RASopathy VCEP-approved KRAS functional assay classes are available, but no variant-specific approved functional result for p.(Met170Leu) was identified in the reviewed functional evidence, so functional pathogenic evidence was not applied.

4

Computational evidence supports a benign prediction because REVEL is 0.294, below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04; BayesDel was 0.164958 as additional computational context.

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 does not fall into the KRAS null-variant categories used for PVS1 assessment.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No previously established pathogenic or likely pathogenic variant with the same amino acid change was identified from the available records, so PS1 is not met.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with the phenotype and parental confirmation was identified, so PS2 cannot be assessed from the available evidence.	clinvar
PS3	Not assessed	Approved KRAS functional assay types are available in the RASopathy VCEP framework, but no variant-specific result for p.(Met170Leu) was identified in the reviewed functional materials, so PS3 cannot be applied.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	No case-control enrichment data or point-based affected-case evidence sufficient for PS4 was identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	p.(Met170Leu) is outside the KRAS RASopathy VCEP PM1 domains (P-loop residues 10-17, Switch I residues 25-40, Switch II residues 57-64, and SAK residues 145-156), and no statistically significant hotspot at residue 170 was identified.	cspec vcep_alignment_with_pm1_domains_pptx hotspots
PM2	Not met	This variant is not absent from controls because it is present in gnomAD v4.1 at 10/1,611,476 alleles (AF 0.00062%), so the KRAS PM2 requirement for absence from controls is not met.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this KRAS RASopathy framework.	cspec
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 is not applicable.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at KRAS codon 170 was identified in the available same-residue review, so PM5 is not met.	pm5_candidates clinvar cspec
PM6	Not assessed	No assumed or unconfirmed de novo report was identified for this variant, so PM6 cannot be assessed from the available evidence.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	clinvar
PP2	N/A	PP2 is not applicable in this KRAS RASopathy framework.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect under the KRAS VCEP rule because REVEL is 0.294, which is below the PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.	revel spliceai bayesdel cspec
PP4	N/A	PP4 is not applicable in this KRAS RASopathy framework.	cspec
PP5	N/A	PP5 is not applicable in this KRAS RASopathy framework.	cspec
BA1	Not met	The population frequency does not meet the BA1 threshold. In gnomAD v4.1 the total allele frequency is 0.00062%, and the highest observed population frequency is 0.01653%, both below the KRAS BA1 threshold of 0.05%.	gnomad_v4 cspec
BS1	Not met	The population frequency is below the KRAS BS1 threshold. In gnomAD v4.1 the total allele frequency is 0.00062% and the highest observed population frequency is 0.01653%, both below the BS1 threshold of 0.025%.	gnomad_v4 cspec
BS2	Not assessed	No point-based evidence from unaffected individuals was identified, so BS2 cannot be assessed.	cspec
BS3	N/A	BS3 is not applicable in this KRAS RASopathy framework.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 cannot be assessed.	clinvar
BP1	N/A	BP1 in this framework is used for truncating variants in genes without established loss-of-function disease correlation; this variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified that this variant occurs with another pathogenic variant in cis or trans in a way that meets the KRAS BP2 point system.	cspec
BP3	N/A	BP3 is not applicable in this KRAS RASopathy framework because no benign repetitive region rule is used.	cspec
BP4	Met	Computational evidence supports BP4. REVEL is 0.294, which is below the KRAS BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. BayesDel is 0.164958 and does not outweigh the VCEP-approved benign computational threshold.	revel spliceai bayesdel cspec
BP5	Not assessed	No alternative molecular explanation or phenotype-based negative point evidence was identified to support BP5.	cspec
BP6	N/A	BP6 is not applicable in this KRAS RASopathy framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable.	cspec

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