Classification rationale

BA1BS1BP6 Benign

KRAS c.531_533del

The KRAS c.531_533del (p.Lys180del) variant has not been observed in COSMIC and is reported in ClinVar as Benign with expert panel review.¹ This variant is present in gnomAD v2.1 at 0.05904% overall and 0.10364% in the highest-frequency subpopulation, and in gnomAD v4.1 at 0.10753% overall and 0.13901% in the highest-frequency subpopulation, exceeding the KRAS RASopathy VCEP BA1 threshold of 0.05% and BS1 threshold of 0.025%.² Computational evidence does not support a disease-relevant splicing effect; SpliceAI showed a maximum delta score of 0.29, and no REVEL or BayesDel score was available for this in-frame deletion.³

BA1 + BS1 + BP6 → Benign

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 · 3 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 · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This in-frame deletion is present in population databases above the KRAS RASopathy VCEP BA1 threshold. In gnomAD v2.1 the overall allele frequency is 0.05904% and the highest observed subpopulation frequency is 0.10364%; in gnomAD v4.1 the overall allele frequency is 0.10753% and the highest observed subpopulation frequency is 0.13901%. These values are above the BA1 threshold of 0.05%, supporting BA1.

gnomAD v2.1 overall AF 0.05904%highest subpopulation AF 0.10364%gnomAD v4.1 overall AF 0.10753%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong Benign

This in-frame deletion is present in population databases above the KRAS RASopathy VCEP BS1 threshold. In gnomAD v2.1 the overall allele frequency is 0.05904% and the highest observed subpopulation frequency is 0.10364%; in gnomAD v4.1 the overall allele frequency is 0.10753% and the highest observed subpopulation frequency is 0.13901%. These values are above the BS1 threshold of 0.025%, supporting BS1.

gnomAD v2.1 overall AF 0.05904%highest subpopulation AF 0.10364%gnomAD v4.1 overall AF 0.10753%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

KRAS RASopathy VCEP marks BP6 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with sufficient parentage information was identified for this variant, so PS2 cannot be assessed from the available evidence.

PS3 No approved variant-specific functional assay result was identified for this exact KRAS in-frame deletion.

PS4 Available evidence does not show enrichment of this variant in affected individuals.

PM1 This variant does not fall within the KRAS RASopathy VCEP PM1 domains.

PM2 This variant is not absent from controls.

PM4 This variant is an in-frame single-amino-acid deletion, but the available evidence does not establish that it should be counted as PM4-level pathogenic evidence in this case.

PM6 No presumed de novo report without full confirmation was identified for this variant, so PM6 cannot be assessed from the available evidence.

PP1 No segregation data were identified for this variant.

PP3 Computational evidence does not support PP3 for this variant.

Benign

BS2 Population data show this variant in gnomAD, including 2 homozygotes in v4.1, but the reviewed materials do not provide the case-based point assessment required by the KRAS RASopathy VCEP BS2 rule.

BS4 No informative non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.

BP1 BP1 in this RASopathy framework is reserved for truncating variants in genes without an established loss-of-function disease correlation.

BP2 No phased occurrence with another variant and no VCEP point-based BP2 evidence were identified for this variant, so BP2 cannot be assessed from the available data.

BP5 No alternative molecular diagnosis or phenotype-discordant explanation was identified for this variant, so BP5 cannot be assessed from the available evidence.

N/A · 11 PVS1 · PS1 · PM3 · PM5 · PP2 · PP4 · PP5 · BS3 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00107527; MAF= 0.10753%, 1732/1610758 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00139014; MAF= 0.13901%, 1637/1177578 alleles, homozygotes = 2); grpmax FAF= 0.00133394.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000590445; MAF= 0.05904%, 166/281144 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00103636; MAF= 0.10364%, 133/128334 alleles, homozygotes = 0); grpmax FAF= 0.00089964.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.11% · 1732 / 1,610,758
2 hom · FAF 0.13%

European (non-Finnish) 1637 / 1,177,578	0.14% 2 hom
Remaining individuals 38 / 62,358	0.061%
African/African American 31 / 74,928	0.041%
Admixed American 9 / 59,890	0.015%
East Asian 5 / 44,718	0.011%
European (Finnish) 6 / 63,958	0.0094%
South Asian 5 / 90,844	0.0055%
Ashkenazi Jewish 1 / 29,538	0.0034%

+ 2 not observed (Amish, Middle Eastern)

gnomAD v2.1

0.059% · 166 / 281,144
0 hom · FAF 0.09%

European (non-Finnish) 133 / 128,334	0.1%
Remaining individuals 4 / 7,176	0.056%
African/African American 13 / 24,820	0.052%
Admixed American 8 / 35,190	0.023%
East Asian 4 / 19,896	0.02%
European (Finnish) 2 / 25,052	0.008%
South Asian 2 / 30,352	0.0066%

+ 1 not observed (Ashkenazi Jewish)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 45129)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).

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 · 4 PMIDs not cited in assessment

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

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

24728327 ↗ Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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