Variant classification summary

NM_001369786.1:c.40G>A

KRAS · NP_001356715.1:p.(Val14Ile) · NM_001369786.1

GRCh37: chr12:25398279 C>T · GRCh38: chr12:25245345 C>T

Gene: KRAS Transcript: NM_001369786.1

Final call

VUS

PP5 supporting PS3 moderate PM1 moderate PM6 supporting PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_001369786.1

Protein

NP_001356715.1:p.(Val14Ile)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.40G>A (p.Val14Ile) variant has been reported in ClinVar as pathogenic, including expert panel review, and it was reported as a de novo germline KRAS mutation in Noonan syndrome.

2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 at 2/1612846 alleles (0.00012%), which is below the KRAS RASopathy VCEP benign frequency thresholds.

3

In the RASopathy VCEP approved functional studies, p.Val14Ile is listed as a pathogenic control in approved RAS activation, MEK activation, and ERK activation assay classes citing PMID:20949621, supporting abnormal KRAS signaling consistent with a gain-of-function effect.

4

Computational data support a damaging missense effect, with REVEL 0.803 above the PP3 threshold of 0.7, BayesDel 0.289645, and SpliceAI showing no significant splice impact (max delta score 0.01).

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
BP7	N/A	This is a missense variant, not a synonymous or non-coding change, so BP7 is not applicable.	cspec
PM5	Not assessed	No same-codon pathogenic missense comparison was identified in the inspected materials, so PM5 was not assessed from the currently reviewed evidence.	cspec
BP5	Not assessed	No alternative molecular diagnosis explaining the phenotype was identified in the inspected evidence, so BP5 was not assessed.	cspec
BP3	N/A	BP3 is not applicable for this VCEP framework.	cspec
PP1	Not assessed	No segregation data with informative meioses were identified, so PP1 was not assessed.	cspec
BS1	Not met	Population frequency is below the BS1 threshold. In gnomAD v4.1 the highest observed frequency is 0.00017% (2/1179292 non-Finnish European alleles), which is below the 0.025% threshold, and the variant is absent from gnomAD v2.1.	cspec gnomad_v2 gnomad_v4
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BP1	N/A	This is a missense variant, whereas BP1 in this VCEP framework is reserved for truncating loss-of-function variants in genes without an established loss-of-function disease correlation.	cspec
BP2	Not assessed	No phase data or second pathogenic variant in the same gene were identified, so BP2 was not assessed.	cspec
BA1	Not met	Population frequency is below the BA1 threshold. In gnomAD v4.1 the total allele frequency is 0.00012% (2/1612846), which is below the 0.05% threshold, and the variant is absent from gnomAD v2.1.	cspec gnomad_v2 gnomad_v4
PS3	Met	In the RASopathy VCEP approved functional studies, KRAS p.(Val14Ile) is listed among pathogenic validation controls in three approved assay classes cited to PMID:20949621: RAS activation, MEK activation, and ERK activation assays. This supports an abnormal KRAS signaling effect consistent with a gain-of-function mechanism.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:20949621
PM4	N/A	This variant does not change protein length, so PM4 is not applicable.	cspec
BS3	N/A	BS3 is not applicable in this VCEP framework.	cspec
PM1	Met	This missense variant affects KRAS residue 14, which lies within the P-loop (amino acids 10-17), a critical and well-established functional domain specified by the RASopathy VCEP for PM1 application.	cspec vcep_alignment_with_pm1_domains_pptx
BS2	Not assessed	No observations in unaffected individuals meeting the VCEP point-based BS2 framework were identified, so BS2 was not assessed.	cspec gnomad_v2 gnomad_v4
PP2	N/A	PP2 is not applicable for this VCEP framework.	cspec
PM6	Met	This variant was reported as a de novo germline KRAS mutation in Noonan syndrome in PMID:16474405. Because confirmation of both maternity and paternity was not identified in the inspected materials, the current evidence supports PM6 at a supporting level rather than PS2.	cspec PMID:16474405 clinvar
BS4	Not assessed	No lack-of-segregation evidence was identified, so BS4 was not assessed.	cspec
PS2	Not met	Available evidence supports a de novo report, but confirmation of both maternity and paternity was not identified in the inspected materials, so PS2 is not met on the current review.	cspec PMID:16474405
PS4	Not assessed	Affected-case observations are suggested by the literature and ClinVar, but the inspected materials did not provide a count of independent probands sufficient for the VCEP point-based PS4 framework, so PS4 was not assessed.	cspec clinvar PMID:16474405 PMID:21784453
PVS1	N/A	PVS1 is not applicable in this VCEP framework, and this missense variant does not fall into the generic null-variant categories used for PVS1.	cspec pvs1_variant_assessment
PS1	Not assessed	No evidence was identified in the inspected materials showing the same amino acid change from a different nucleotide change, so PS1 was not assessed.	cspec
PM3	N/A	PM3 is not applicable in this VCEP framework.	cspec
PP4	N/A	PP4 is not applicable in this VCEP framework because phenotype-based case evidence is handled through PS4.	cspec
PM2	Not met	The VCEP requires absence from controls for PM2. This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 0.00012% (2/1612846 alleles), so the absence requirement is not met.	cspec gnomad_v2 gnomad_v4
BP4	Not met	Benign computational evidence is not met. REVEL is 0.803, which is above the BP4 threshold of 0.3, although SpliceAI predicts no significant splice impact with a max delta score of 0.01.	cspec revel spliceai bayesdel
PP3	Met	Computational evidence supports a deleterious missense effect. REVEL is 0.803, which is above the VCEP PP3 threshold of 0.7, BayesDel is 0.289645, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a missense rather than splicing mechanism.	cspec revel bayesdel spliceai
BP6	N/A	BP6 is not used in this VCEP framework.	cspec

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