Variant classification summary

NM_001369787.1:c.519T>C

KRAS · NP_001356716.1:p.(Asp173=) · NM_001369787.1

GRCh37: chr12:25362777 A>G · GRCh38: chr12:25209843 A>G

Gene: KRAS Transcript: NM_001369787.1

Final call

Benign

BA1 stand-alone benign BP6 supporting benign

Variant details

Gene

KRAS

Transcript

NM_001369787.1

Protein

NP_001356716.1:p.(Asp173=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.519T>C (p.Asp173=; p.D173=) variant has been reported in ClinVar as Benign, including by the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is common in population databases, with an allele frequency of 19.06% in gnomAD v2.1 and 20.60% in gnomAD v4.1, which is far above the KRAS RASopathy VCEP BA1 benign threshold of 0.05%.

3

In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.10.

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 synonymous KRAS variant is present at a population frequency far above the benign stand-alone threshold. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, which is well above the KRAS RASopathy VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Population frequency also exceeds the BS1 threshold, but BA1 is already met and is the more appropriate population rule for this variant. Separate BS1 application would not add clinically meaningful evidence beyond BA1.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	This variant is common in population databases, including many homozygotes, but no phenotype-linked adult observation data were identified to assign the KRAS RASopathy VCEP BS2 point-based rule directly.	cspec gnomad_v2 gnomad_v4
BS3	N/A	The KRAS RASopathy VCEP marks BS3 as not applicable.	cspec
BS4	Not assessed	No family data showing lack of segregation were identified for this variant.	cspec
BP1	N/A	This rule is reserved in the KRAS RASopathy specification for truncating variants in genes without an established loss-of-function disease correlation. This variant is synonymous and is not a truncating variant.	cspec
BP2	Not assessed	No phase data or point-based evidence for occurrence with another causative variant were identified for this variant.	cspec
BP3	N/A	The KRAS RASopathy VCEP marks BP3 as not applicable because no known benign repetitive regions are defined for this context.	cspec
BP4	N/A	In the KRAS RASopathy specification, BP4 is defined for missense variants with REVEL <=0.3. This variant is synonymous, not missense, and no REVEL or BayesDel score was available.	cspec
BP5	Not assessed	No evidence was identified for an alternative molecular explanation or phenotype inconsistency meeting the KRAS RASopathy VCEP point-based BP5 rule.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Not assessed	This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. However, the KRAS RASopathy VCEP BP7 rule also requires that the nucleotide not be highly conserved, and no conservation evidence was identified here.	cspec spliceai
PP1	Not assessed	No segregation data were identified for this variant.	cspec
PP2	N/A	The KRAS RASopathy VCEP marks PP2 as not applicable.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which does not support an abnormal splicing outcome consistent with disease mechanism; REVEL and BayesDel scores were not available.	cspec spliceai
PP4	N/A	The KRAS RASopathy VCEP marks PP4 as not applicable.	cspec
PP5	N/A	The KRAS RASopathy VCEP marks PP5 as not applicable.	cspec
PS1	N/A	This variant is synonymous and does not create an amino acid change, so the same-amino-acid pathogenic substitution rule does not apply.	cspec
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	cspec
PS3	Not assessed	No approved variant-specific functional assay evidence was identified for this synonymous KRAS variant.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not met	Available evidence does not support enrichment in affected individuals. This variant is common in population databases, so the KRAS RASopathy VCEP PM2 absence-from-controls requirement that precedes PS4 is not met.	cspec gnomad_v2 gnomad_v4
PM1	Not met	This variant does not fall within the KRAS RASopathy VCEP PM1 functional domain ranges of amino acids 10-17, 25-40, 57-64, or 145-156. The synonymous residue Asp173 is outside these specified domains, and no hotspot evidence supporting codon 173 was identified.	cspec hotspots
PM2	Not met	This variant is not absent from controls. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, so the KRAS RASopathy VCEP PM2 absence-from-controls requirement is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	The KRAS RASopathy VCEP marks PM3 as not applicable.	cspec
PM4	N/A	This variant is a synonymous single-nucleotide substitution and does not produce a protein length change or in-frame insertion/deletion.	cspec
PM5	N/A	This variant is synonymous and does not create a novel amino acid substitution at codon 173, so the same-codon different-pathogenic-missense rule does not apply.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	cspec
PVS1	N/A	The KRAS RASopathy VCEP marks PVS1 as not applicable for this framework, and this variant is a synonymous substitution rather than a nonsense, frameshift, or canonical +/-1,2 splice variant.	cspec pvs1_gene_context pvs1_variant_assessment

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