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 ↗

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= 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