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KRAS
Final classification
Benign
KRAS c.531_533del · p.Lys180del
KRAS

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.

Gene
KRAS
Transcript
NM_001369787.1
HGVS · transcript:coding
NM_001369787.1:c.531_533del
Consequence
N/A
GRCh38
chr12:25209828 TTTC>T
GRCh37
chr12:25362762 TTTC>T
Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP6 supporting benign; maps to Benign. ▾
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP6 supporting benign; maps to Benign.
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 ↗
Gene diagram · NM_001369787.1 · variants mapped to exon structure
KRAS NM_001369787.1
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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 screenshot
      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 ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).
      SpliceAI ↗
      Functional / OncoKB screenshot
      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 screenshot
      COSMIC
      Cancer hotspots screenshot
      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