Variant classification summary

NM_001369787.1:c.531_533del

KRAS · NP_001356716.1:p.(Lys180del) · NM_001369787.1

GRCh37: chr12:25362762 TTTC>T · GRCh38: chr12:25209828 TTTC>T

Gene: KRAS Transcript: NM_001369787.1

Final call

Benign

BA1 stand-alone benign BS1 strong BP6 supporting benign

Variant details

Gene

KRAS

Transcript

NM_001369787.1

Protein

NP_001356716.1:p.(Lys180del)

gnomAD AF

0.001075270152313383 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BA1	Met	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 gnomad_v4 cspec
BS1	Met	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 gnomad_v4 cspec
PM2	Not met	This variant is not absent from controls. It is present in gnomAD v2.1 at 0.05904% overall and in gnomAD v4.1 at 0.10753% overall, so the PM2 requirement for absence from controls is not met.	gnomad_v2 gnomad_v4 cspec
PVS1	N/A	PVS1 is not applicable in this KRAS RASopathy framework, and the variant-specific PVS1 review found that this change is an in-frame deletion rather than a nonsense, frameshift, or canonical splice variant.	cspec pvs1_gene_context pvs1_variant_assessment
PM1	Not met	This variant does not fall within the KRAS RASopathy VCEP PM1 domains. The affected residue is Lys180, which is outside the specified P-loop (amino acids 10-17), switch I (25-40), switch II (57-64), and SAK (145-156) regions, so PM1 is not met.	cspec
PM4	Not assessed	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. The reviewed materials do not provide variant-specific evidence showing that this protein-length change has a disease-causing effect independent of the strong benign population data.	cspec gnomad_v2 gnomad_v4 clinvar
PS3	Not assessed	No approved variant-specific functional assay result was identified for this exact KRAS in-frame deletion. The reviewed KRAS functional-study materials list approved assay types for the gene, but they do not provide a variant-specific approved assay result for p.Lys180del that would support PS3.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals. The variant is classified as Benign in ClinVar with expert panel review, is not reported in COSMIC, and is present in gnomAD at frequencies above benign thresholds, so PS4 is not met.	clinvar gnomad_v2 gnomad_v4
PS2	Not assessed	No confirmed de novo occurrence with sufficient parentage information was identified for this variant, so PS2 cannot be assessed from the available evidence.	clinvar
PM6	Not assessed	No presumed de novo report without full confirmation was identified for this variant, so PM6 cannot be assessed from the available evidence.	clinvar
PP1	Not assessed	No segregation data were identified for this variant. There is no evidence of co-segregation across informative meioses, so PP1 cannot be assessed.	clinvar
BS4	Not assessed	No informative non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.	clinvar
BS2	Not assessed	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. BS2 therefore remains unassessed here.	gnomad_v4 cspec
PP3	Not met	Computational evidence does not support PP3 for this variant. REVEL and BayesDel are not available for this in-frame deletion, and SpliceAI shows a maximum delta score of 0.29, which does not by itself establish a predicted splice effect matching the KRAS RASopathy disease mechanism.	spliceai cspec
BP4	N/A	BP4 is specified by this framework for missense variants with REVEL 0.3 or lower. This variant is an in-frame deletion rather than a missense change, and no framework-specific benign computational rule was identified for this variant class.	cspec spliceai
PS1	N/A	PS1 is a same-amino-acid-change rule for variants producing an already established pathogenic amino acid substitution. This variant is an in-frame deletion, not an alternate nucleotide change causing the same amino acid substitution, so PS1 is not applicable.	cspec
PM5	N/A	The KRAS RASopathy VCEP uses classic same-residue missense PM5 logic. This variant is an in-frame deletion rather than a missense change, and the PM5 candidate review marked it as not applicable for this variant class.	cspec pm5_candidates
BP1	Not met	BP1 in this RASopathy framework is reserved for truncating variants in genes without an established loss-of-function disease correlation. This variant is an in-frame deletion and does not meet that condition, so BP1 is not met.	cspec
BP2	Not assessed	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.	cspec
BP5	Not assessed	No alternative molecular diagnosis or phenotype-discordant explanation was identified for this variant, so BP5 cannot be assessed from the available evidence.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PM3	N/A	PM3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP4	N/A	PP4 is not applicable in the KRAS RASopathy VCEP framework.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	N/A	BP7 is intended for synonymous, intronic, or non-coding variants with no predicted splice effect. This variant is an in-frame coding deletion, so BP7 is not applicable.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.