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.1 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%.2 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.3 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.4
Final classification
VUS
BP4
KRAS
c.508A>T
p.Met170Leu
This variant
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: BP4 supporting; no rule matched the adjudicated criteria.
Classification rationale
BP4
VUS
KRAS c.508A>T
BP4
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelspliceai ↗bayesdelcspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001369787.1 · variants mapped to exon structure
KRAS
NM_001369787.1
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BP4
supporting
Benign
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 score 0.294.SpliceAI max delta 0.04.BayesDel score 0.164958.
Assessed · not applied
· 7 not met · 9 not assessed
Pathogenic
PS1
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.
PS2
No confirmed de novo occurrence with the phenotype and parental confirmation was identified, so PS2 cannot be assessed from the available evidence.
PS3
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.
PS4
No case-control enrichment data or point-based affected-case evidence sufficient for PS4 was identified.
PM1
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.
PM2
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.
PM5
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.
PM6
No assumed or unconfirmed de novo report was identified for this variant, so PM6 cannot be assessed from the available evidence.
PP1
No segregation data were identified for this variant, so PP1 cannot be assessed.
PP3
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.
Benign
BA1
The population frequency does not meet the BA1 threshold.
BS1
The population frequency is below the KRAS BS1 threshold.
BS2
No point-based evidence from unaffected individuals was identified, so BS2 cannot be assessed.
BS4
No nonsegregation data were identified for this variant, so BS4 cannot be assessed.
BP2
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.
BP5
No alternative molecular explanation or phenotype-based negative point evidence was identified to support BP5.
N/A · 11
PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.20549e-06; MAF= 0.00062%, 10/1611476 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165289; MAF= 0.01653%, 1/6050 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00062%
· 10 / 1,611,476
0 hom · FAF 0.00036%
0 hom · FAF 0.00036%
Middle Eastern 1 / 6,050 |
0.017% |
European (non-Finnish) 9 / 1,178,008 |
0.00076% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 180859)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.294. BayesDel score = 0.164958.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR