Variant classification summary

NM_004985.5:c.35G>C

KRAS · NP_004976.2:p.(Gly12Ala) · NM_004985.5

GRCh37: chr12:25398284 C>G · GRCh38: chr12:25245350 C>G

Gene: KRAS Transcript: NM_004985.5

Final call

VUS

PS3 supporting PM1 moderate PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Gly12Ala)

gnomAD AF

1.2400286198605464e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: KRAS p.Gly12Ala showed approximately 40- to 80-fold lower intrinsic GTP hydrolysis than wild type.

2

PM1 moderate: residue 12 lies within the KRAS VCEP-approved P-loop domain spanning amino acids 10-17.

3

PP3 supporting: REVEL 0.841 meets the VCEP missense threshold of at least 0.7.

Final determination: Under the KRAS VCEP Version 2.3 criteria-combination framework, no pathogenic or benign rule is met by one moderate criterion and two supporting criteria, so the result is VUS.

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	Not applicable: the VCEP marks PVS1 not applicable, and this is a missense c.35G>C variant producing p.(Gly12Ala).	cspec pvs1_variant_assessment
PS1	Not met	Not met: the evidence establishes KRAS p.Gly12Ala itself, but no separately nucleotide-different pathogenic variant with the same amino-acid change was identified.	cspec clinvar vcep_alignment_with_pm1_domains_pptx
PS2	Not assessed	Not assessed: no documented proband, parental testing, confirmed de novo status, or PS2 point assignment is available to reach the VCEP's 1-, 2-, or 4-point thresholds.	cspec
PS3	Met	Met at Supporting: KRAS G12A showed approximately 40- to 80-fold lower intrinsic GTP hydrolysis than wild type in a variant-specific biochemical study.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:26037647
PS4	Not met	Not met: no qualifying RASopathy case-control enrichment or VCEP phenotype points were documented, so the available score is 0 versus the ≥1-point Supporting threshold.	cspec PMID:15696205 PMID:23182985 PMID:26662311
PM1	Met	Met at Moderate: KRAS residue 12 lies within the VCEP-approved P-loop critical domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: the variant is present in default all-comers gnomAD v4.1 at 2/1,612,866 alleles, not absent from controls.	cspec gnomad_v4
PM3	N/A	Not applicable: the KRAS VCEP explicitly designates PM3 as not applicable.	cspec
PM4	Not met	Not met: c.35G>C causes p.(Gly12Ala) without an in-frame indel, stop-loss consequence, or protein-length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the comparator search yielded zero codon-12 same-residue candidates, so neither the one-variant nor two-variant PM5 threshold can be evaluated.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no apparently de novo occurrence without parental testing or PM6 point assignment is documented to reach the VCEP's 0.5-, 1-, or 2-point thresholds.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP PP1 thresholds of 3, 5, or 7 meioses can be evaluated.	cspec
PP2	N/A	Not applicable: the KRAS VCEP explicitly excludes PP2 from use.	cspec
PP3	Met	Met: REVEL 0.841 meets the VCEP PP3 missense threshold of >=0.7; the separate splicing path is not required in combination.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP explicitly excludes PP4 and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP states that PP5 is not for use under the VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: gnomAD v4.1 AF is 0.00012%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 AF is 0.00012%, below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no evidence establishes healthy adult carrier status or supplies the VCEP's required BS2 point score.	cspec gnomad_v4
BS3	N/A	Not applicable: the KRAS VCEP v2.3 explicitly marks BS3 as not applicable, regardless of available functional assay results.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis with a tested unaffected relative lacking the variant is documented for the VCEP's single-meiosis requirement.	cspec
BP1	N/A	Not applicable: BP1 is restricted to specified truncating variants, whereas this variant is a missense substitution p.Gly12Ala.	cspec
BP2	Not assessed	Not assessed: no documented second pathogenic KRAS variant, cis/trans phase, affected-proband observation, or RASopathy severity assessment is available to assign BP2 points.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable, and this variant is a missense substitution rather than a repetitive-region in-frame indel.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.841 exceeds the VCEP BP4 missense cutoff of <=0.3.	cspec revel
BP5	Not met	Not met: no alternative causative variant or different-gene molecular cause was documented, yielding 0 points versus the ≥(-1)-point Supporting threshold.	cspec
BP6	N/A	Not applicable: the KRAS VCEP states that BP6 is not for use under the VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, noncanonical intronic, or non-coding variants, whereas c.35G>C is missense.	cspec pvs1_variant_assessment

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