Variant classification summary

NM_001369786.1:c.15A>T

KRAS · NP_001356715.1:p.(Lys5Asn) · NM_001369786.1

GRCh37: chr12:25398304 T>A · GRCh38: chr12:25245370 T>A

Gene: KRAS Transcript: NM_001369786.1

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

KRAS

Transcript

NM_001369786.1

Protein

NP_001356715.1:p.(Lys5Asn)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.15A>T (p.(Lys5Asn), p.(K5N)) variant has been observed in somatic cancers in COSMIC (COSV56100680, 2 occurrences) and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases.

3

In approved functional studies used by the RASopathy VCEP, p.(Lys5Asn) showed abnormal results in both MEK activation and ERK activation assays, and published KRAS functional work described aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect.

4

Computational evidence supports a deleterious missense effect because REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.19; BayesDel is 0.0213364.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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
PVS1	N/A	This is a missense variant and does not fall into the null-variant categories used for PVS1. The variant-specific PVS1 assessment states that it is not a nonsense, frameshift, or canonical ±1/2 splice variant, and the KRAS RASopathy specification marks PVS1 as not applicable for this variant type.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No retrieved evidence established a different nucleotide change producing the same KRAS p.(Lys5Asn) amino acid substitution as a previously established pathogenic variant, so PS1 was not applied.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental relationship and testing details was identified in the retrieved evidence, so PS2 was not applied.	cspec
PS3	Met	Approved KRAS functional studies in the RASopathy VCEP materials list p.(Lys5Asn) among pathogenic variants showing abnormal results in two different approved assays, MEK activation and ERK activation, and the cited KRAS functional literature describes aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect. This supports PS3 at the Moderate level under the KRAS RASopathy specification.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:20949621
PS4	Not assessed	Although this variant is present in ClinVar and has been observed in somatic cancers, the retrieved evidence did not provide the point-based proband counts or enrichment data required by the KRAS RASopathy specification for PS4. PS4 was therefore not applied.	cspec clinvar oncokb PMID:20949621
PM1	Not met	The KRAS RASopathy specification limits PM1 to the P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156) domains. p.(Lys5Asn) affects codon 5, which is outside these specified domains, so PM1 is not met.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the KRAS RASopathy specification, absence from controls supports PM2 at the Supporting level.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the KRAS RASopathy specification for this condition framework.	cspec
PM4	N/A	This is not an in-frame insertion/deletion or protein length-changing variant, so PM4 is not applicable.	cspec
PM5	Not assessed	The retrieved evidence did not document a different established pathogenic missense change at KRAS codon 5 with the case-count detail needed to assign PM5 under the KRAS RASopathy specification, so PM5 was not applied.	cspec clinvar
PM6	Not assessed	No presumed or confirmed de novo evidence with sufficient case-level detail was identified in the retrieved materials, so PM6 was not applied.	cspec
PP1	Not assessed	No segregation data were identified showing that this variant tracks with disease across informative meioses, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy specification.	cspec
PP3	Met	For this missense variant, REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of at least 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.19, supporting interpretation as a missense rather than splicing mechanism, and BayesDel is also available at 0.0213364. These data support PP3 at the Supporting level.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in the KRAS RASopathy specification for this framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BA1 threshold of at least 0.05% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BS1 threshold of at least 0.025% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at the point level required by the KRAS RASopathy specification, so BS2 was not applied.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy specification.	cspec
BS4	Not assessed	No non-segregation data were identified showing this variant in unaffected relatives or lack of tracking with disease, so BS4 was not applied.	cspec
BP1	N/A	In the KRAS RASopathy specification, BP1 is reserved for truncating or canonical splice variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No phase information or alternative molecular diagnosis evidence was identified to support BP2, so this criterion was not applied.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy specification because no known benign repetitive regions are defined for this use.	cspec
BP4	Not met	For missense variants, the KRAS RASopathy BP4 threshold requires REVEL of 0.3 or lower. This variant has a REVEL score of 0.764, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice impact with a maximum delta score of 0.19, but that does not override the missense-specific REVEL threshold.	cspec revel spliceai
BP5	Not assessed	No alternative molecular explanation or phenotype-based point evidence was identified to support BP5, so this criterion was not applied.	cspec
BP6	N/A	BP6 is not applicable in the KRAS RASopathy specification.	cspec
BP7	N/A	BP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact. This is a missense variant, so BP7 is not applicable.	cspec spliceai

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