Classification rationale

BP4 VUS

KRAS c.508A>T

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

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studies

4 revelspliceai ↗bayesdelcspec ↗

Gene diagram · NM_001369787.1 · variants mapped to exon structure

KRAS NM_001369787.1

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.294. BayesDel score = 0.164958.

SpliceAI ↗

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

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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