Classification rationale

BP6 VUS

KRAS c.451-14T>C

The KRAS c.451-14T>C (p.?) variant has been reported in ClinVar as Likely Benign, including an expert-panel likely benign assertion from the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in population databases, including gnomAD v2.1 at 0.00398% (11/276052 alleles) and gnomAD v4.1 at 0.01100% (175/1591272 alleles), which is above the PM2 absence requirement but below the KRAS RASopathy VCEP BS1 threshold of 0.025% and BA1 threshold of 0.05%.² SpliceAI predicts no significant splice impact for this intronic change, with a maximum delta score of 0.01, which does not support PP3 and leaves BP7 incomplete without the additional conservation evidence required by the VCEP rule.³

BP6 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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 · 14 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

BP6 supporting review Benign

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

KRAS RASopathy VCEP marks BP6 not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with phenotype specificity and parental confirmation was identified for this variant, so PS2 cannot currently be applied.

PS3 No approved functional assay, RNA study, or other direct experimental evidence demonstrating an abnormal effect of this specific intronic variant was identified, so PS3 is not met.

PS4 No affected-case enrichment or point-based case evidence for this exact variant was identified, and the variant is present in gnomAD, so PS4 is not currently supported.

PM2 This variant is present in gnomAD v2.1 at 0.00398% (11/276052 alleles) and in gnomAD v4.1 at 0.01100% (175/1591272 alleles), so it is not absent from controls and PM2_Supporting is not met.

PM6 No apparently de novo report without full parental confirmation was identified for this exact variant, so PM6 cannot currently be applied.

PP1 No segregation data for this exact variant were identified, so PP1 is not currently supported.

PP3 SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which does not support a splicing impact consistent with disease mechanism; no REVEL score is available because this is not a missense variant.

Benign

BA1 The highest observed filtering allele frequency is below the BA1 threshold of 0.05%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BA1 is not met.

BS1 The highest observed filtering allele frequency is below the BS1 threshold of 0.025%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BS1 is not met.

BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals sufficient to score BS2 under the RASopathy VCEP point system.

BS4 No non-segregation data for this exact variant were identified, so BS4 is not currently supported.

BP2 No evidence was identified for this variant occurring with another pathogenic RASopathy variant in cis or trans in a manner that would score BP2.

BP5 No alternative molecular diagnosis or other point-scoring evidence sufficient for BP5 was identified for this variant.

BP7 This non-canonical intronic variant has SpliceAI scores consistent with no meaningful splice disruption (maximum delta score 0.01), but the reviewed evidence did not establish the nucleotide as not highly conserved and the VCEP notes BP7 should be used in conjunction with BP4 for intronic or non-coding variants, so BP7 is not applied at this time.

N/A · 13 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000109975; MAF= 0.01100%, 175/1591272 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000135432; MAF= 0.01354%, 10/73838 alleles, homozygotes = 0); grpmax FAF= 0.00011553.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98476e-05; MAF= 0.00398%, 11/276052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000142491; MAF= 0.01425%, 1/7018 alleles, homozygotes = 0); grpmax FAF= 3.979e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.011% · 175 / 1,591,272
0 hom · FAF 0.012%

African/African American 10 / 73,838	0.014%
European (non-Finnish) 155 / 1,163,850	0.013%
Remaining individuals 8 / 61,612	0.013%
Admixed American 2 / 58,702	0.0034%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.004% · 11 / 276,052
0 hom · FAF 0.004%

Remaining individuals 1 / 7,018	0.014%
African/African American 2 / 24,414	0.0082%
European (non-Finnish) 8 / 126,988	0.0063%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory) 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 = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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