NM_001369787.1:c.451-14T>C

KRAS · NP_001356716.1:p.? · NM_001369787.1

GRCh37: chr12:25362859 A>G · GRCh38: chr12:25209925 A>G

Gene: KRAS Transcript: NM_001369787.1

Final call

VUS

BP6 supporting benign

Variant details

Gene

KRAS

Transcript

NM_001369787.1

Protein

NP_001356716.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The KRAS c.451-14T>C (p.?) variant has been reported in ClinVar as Likely Benign, including an expert-panel likely benign assertion from the ClinGen RASopathy Variant Curation Expert Panel.

This variant is present in population databases, including gnomAD v2.1 at 0.00398% (11/276052 alleles) and gnomAD v4.1 at 0.01100% (175/1591272 alleles), which is above the PM2 absence requirement but below the KRAS RASopathy VCEP BS1 threshold of 0.025% and BA1 threshold of 0.05%.

SpliceAI predicts no significant splice impact for this intronic change, with a maximum delta score of 0.01, which does not support PP3 and leaves BP7 incomplete without the additional conservation evidence required by the VCEP rule.

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 intronic c.451-14T>C variant is outside the canonical +/-1,2 splice positions and does not fall into the null-variant categories used for PVS1; the KRAS RASopathy VCEP also lists PVS1 as not applicable for this variant type.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant is intronic and has no established protein change, so there is no same-amino-acid substitution evidence to evaluate under PS1.	cspec
PS2	Not assessed	No confirmed de novo occurrence with phenotype specificity and parental confirmation was identified for this variant, so PS2 cannot currently be applied.	cspec
PS3	Not assessed	No approved functional assay, RNA study, or other direct experimental evidence demonstrating an abnormal effect of this specific intronic variant was identified, so PS3 is not met.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	No affected-case enrichment or point-based case evidence for this exact variant was identified, and the variant is present in gnomAD, so PS4 is not currently supported.	cspec gnomad_v2 gnomad_v4
PM1	N/A	This variant is intronic and does not alter an amino acid within the KRAS PM1 functional domains, so PM1 is not applicable.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	This variant is present in gnomAD v2.1 at 0.00398% (11/276052 alleles) and in gnomAD v4.1 at 0.01100% (175/1591272 alleles), so it is not absent from controls and PM2_Supporting is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the KRAS RASopathy VCEP framework for this disorder context.	cspec
PM4	N/A	This intronic substitution does not cause an in-frame protein length change or stop-loss event, so PM4 is not applicable.	cspec
PM5	N/A	This variant is intronic and does not create a novel missense change at a codon with other pathogenic substitutions, so PM5 is not applicable.	cspec
PM6	Not assessed	No apparently de novo report without full parental confirmation was identified for this exact variant, so PM6 cannot currently be applied.	cspec
PP1	Not assessed	No segregation data for this exact variant were identified, so PP1 is not currently supported.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP3	Not met	SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which does not support a splicing impact consistent with disease mechanism; no REVEL score is available because this is not a missense variant.	cspec spliceai
PP4	N/A	PP4 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	The highest observed filtering allele frequency is below the BA1 threshold of 0.05%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The highest observed filtering allele frequency is below the BS1 threshold of 0.025%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped unaffected individuals sufficient to score BS2 under the RASopathy VCEP point system.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
BS4	Not assessed	No non-segregation data for this exact variant were identified, so BS4 is not currently supported.	cspec
BP1	N/A	BP1 in this VCEP is intended for truncating or loss-of-function variants in genes where gain-of-function is the main disease mechanism; this non-canonical intronic variant is not a truncating loss-of-function variant.	cspec
BP2	Not assessed	No evidence was identified for this variant occurring with another pathogenic RASopathy variant in cis or trans in a manner that would score BP2.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
BP4	N/A	The KRAS RASopathy VCEP BP4 rule is defined for missense variants using REVEL <=0.3, and this intronic variant has no missense consequence or REVEL score.	cspec spliceai
BP5	Not assessed	No alternative molecular diagnosis or other point-scoring evidence sufficient for BP5 was identified for this variant.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not assessed	This non-canonical intronic variant has SpliceAI scores consistent with no meaningful splice disruption (maximum delta score 0.01), but the reviewed evidence did not establish the nucleotide as not highly conserved and the VCEP notes BP7 should be used in conjunction with BP4 for intronic or non-coding variants, so BP7 is not applied at this time.	cspec spliceai

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