Classification rationale

BS1BA1BP4BP6 Benign

KRAS c.24A>G

The KRAS c.24A>G (p.Val8=) variant has been reported in ClinVar with an expert panel classification of likely benign, with additional benign and likely benign clinical laboratory submissions.¹ This variant is present in population databases at a frequency above the KRAS VCEP benign thresholds, with grpmax filtering allele frequencies of 0.0402% in gnomAD v2.1 and 0.056632% in gnomAD v4.1, exceeding the BS1 threshold of 0.025% and the BA1 threshold of 0.05% in v4.1.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, supporting no expected clinically meaningful effect on splicing.³

BS1 + BA1 + BP4 + BP6 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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_004985.4 · variants mapped to exon structure

KRAS NM_004985.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 17 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant is present in gnomAD above the KRAS VCEP BA1 threshold of 0.05% filtering allele frequency. The gnomAD v4.1 grpmax FAF is 0.056632%, which is above the BA1 threshold.

gnomAD v4.1 grpmax FAF 0.00056632 (0.056632%)KRAS VCEP BA1 threshold >=0.05%

cspec ↗gnomad_v4 ↗

BS1 strong Benign

This variant is present in gnomAD above the KRAS VCEP BS1 threshold of 0.025% filtering allele frequency. The observed grpmax FAF is 0.0402% in gnomAD v2.1 and 0.056632% in gnomAD v4.1, both above the BS1 threshold.

gnomAD v2.1 grpmax FAF 0.000402 (0.0402%)gnomAD v4.1 grpmax FAF 0.00056632 (0.056632%)KRAS VCEP BS1 threshold >=0.025%

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.02, which supports a negligible effect on splicing and meets BP4 at supporting strength.

SpliceAI DS_AG 0.01SpliceAI DS_AL 0.02SpliceAI DS_DG 0.00

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.

KRAS VCEP marks BP6 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 9 not met · 8 not assessed

Pathogenic

PS1 This variant does not change the amino acid sequence, so it does not meet PS1 for the same amino acid change as a previously established pathogenic variant.

PS2 No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant, so PS2 could not be assessed.

PS3 No approved variant-specific functional study was identified showing a damaging effect for this synonymous KRAS variant, so PS3 is not met.

PS4 No evidence was identified that this variant is enriched in individuals with a KRAS-related RASopathy, and no exact proband count meeting the KRAS VCEP point thresholds was found, so PS4 is not met.

PM1 Codon 8 is outside the KRAS VCEP PM1 domains P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156), and no hotspot evidence was identified for this residue, so PM1 is not met.

PM2 This variant is present in gnomAD and therefore does not meet the KRAS VCEP PM2 rule requiring absence from controls.

PM4 This variant does not alter protein length and is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 is not met.

PM5 This variant is synonymous and does not create a novel amino acid substitution, so it does not meet the KRAS VCEP PM5 rule for a different missense change at the same codon.

PM6 No assumed de novo report without confirmed parentage was identified for this variant, so PM6 could not be assessed.

PP1 No segregation data were identified for this variant, so PP1 could not be assessed.

PP3 Available computational evidence does not support a deleterious effect.

Benign

BS2 Population frequency data alone do not establish observation in clinically evaluated unaffected individuals under the KRAS VCEP BS2 point-based framework, so BS2 was not assessed.

BS4 No informative non-segregation data were identified for this variant, so BS4 could not be assessed.

BP1 This variant is a synonymous substitution rather than a truncating loss-of-function variant, so it does not meet the KRAS VCEP BP1 rule.

BP2 No phase data or evidence of another pathogenic RASopathy variant in the same gene were identified, so BP2 could not be assessed.

BP5 No evidence was identified for an alternative molecular explanation of a RASopathy phenotype in another gene, so BP5 could not be evaluated.

BP7 This synonymous variant has no predicted splice effect by SpliceAI (max delta score 0.02), but the KRAS VCEP rule for BP7 also requires that the altered nucleotide is not highly conserved, and no conservation evidence was identified here.

N/A · 7 PVS1 · PM3 · PP2 · PP4 · PP5 · BS3 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000460165; MAF= 0.04602%, 742/1612464 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000603834; MAF= 0.06038%, 712/1179132 alleles, homozygotes = 0); grpmax FAF= 0.00056632.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000253604; MAF= 0.02536%, 71/279964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000509524; MAF= 0.05095%, 65/127570 alleles, homozygotes = 0); grpmax FAF= 0.000402.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.046% · 742 / 1,612,464
0 hom · FAF 0.057%

European (non-Finnish) 712 / 1,179,132	0.06%
Remaining individuals 23 / 62,406	0.037%
African/African American 5 / 74,930	0.0067%
Admixed American 1 / 59,894	0.0017%
European (Finnish) 1 / 63,990	0.0016%

+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.025% · 71 / 279,964
0 hom · FAF 0.04%

European (non-Finnish) 65 / 127,570	0.051%
Remaining individuals 3 / 7,176	0.042%
African/African American 2 / 24,702	0.0081%
European (Finnish) 1 / 25,044	0.004%

+ 4 not observed (Admixed American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99778613, n = 1 times).

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

Check your email

Reset your password

Enter an access code

Your allowance