Variant classification summary

NM_004985.5:c.436G>A

KRAS · NP_004976.2:p.(Ala146Thr) · NM_004985.5

GRCh37: chr12:25378562 C>T · GRCh38: chr12:25225628 C>T

Gene: KRAS Transcript: NM_004985.5

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM5 moderate PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Ala146Thr)

gnomAD AF

1.860079834626502e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: A146T is a P/LP control in two approved functional assay types.

2

PM1 Moderate: residue 146 lies in the approved SAK critical domain (145–156).

3

PM5 Moderate: p.Ala146Val is an alternate likely pathogenic change at codon 146.

4

PP3 Supporting: REVEL 0.909 exceeds the VCEP threshold of 0.7.

Final determination: KRAS VCEP Rule14 is satisfied by two Moderate criteria (PM1 and PM5) plus at least two Supporting criteria (PS3 counted at its lower Supporting requirement and PP3), yielding Likely Pathogenic.

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: c.436G>A is a missense p.(Ala146Thr) substitution, whereas the VCEP marks PVS1 not applicable for this variant framework.	cspec pvs1_variant_assessment
PS1	Not met	Not met: the reviewed reports describe KRAS c.436G>A p.Ala146Thr itself, with no distinct nucleotide change producing the same amino-acid substitution.	cspec
PS2	Not assessed	Not assessed: no documented proband-level de novo result with confirmed maternity and paternity and sufficient phenotype information is available.	cspec
PS3	Met	Met, Moderate: A146T is a P/LP validation control in two different approved assays, RAS activation and ERK activation, satisfying the VCEP's two-assay rule.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:20147967 PMID:20570890
PS4	Not met	Not met: available reports lack a qualifying RASopathy case-control comparison, and gnomAD v4.1 contains the variant at 3/1,612,834 alleles.	cspec PMID:20147967 PMID:20570890 gnomad_v4
PM1	Met	Met at Moderate: KRAS residue 146 lies within the VCEP-approved SAK critical domain spanning amino acids 145-156.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: the variant is present in all-comers gnomAD v4.1 at AF 1.86008e-06, whereas PM2 requires absence from gnomAD controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the KRAS VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.(Ala146Thr) is a missense substitution with no in-frame indel, stop-loss, or protein-length change required by the VCEP PM4 rule.	cspec pvs1_variant_assessment
PM5	Met	Met at Moderate: PMID:26970110 reports one alternate oncogenic KRAS residue change, p.Ala146Val, at the same codon 146.	cspec
PM6	Not assessed	Not assessed: no assumed de novo proband observation or parental testing is documented for this variant.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so the VCEP thresholds of 3, 5, or 7 informative meioses cannot be evaluated.	cspec
PP2	N/A	Not applicable: the KRAS VCEP excludes PP2 because the missense z score is below 3.09 in gnomAD.	cspec
PP3	Met	Met: REVEL 0.909 meets the KRAS VCEP PP3 missense threshold of >=0.7.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP explicitly directs phenotype-specific evidence to PS4 instead of PP4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP prohibits use of PP5 for this VCEP.	cspec
BA1	Not met	Not met: the highest all-comers gnomAD v4.1 frequency is 0.00160%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest all-comers gnomAD v4.1 frequency is 0.00160%, below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no VCEP-usable healthy-individual phenotype or point-based BS2 assignment is available.	cspec gnomad_v4
BS3	N/A	Not applicable: the KRAS VCEP marks BS3 not applicable, and its approved assay table assigns BS3_NA for the A146T-containing assay entries.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis demonstrating non-segregation in an affected family member is documented.	cspec
BP1	N/A	Not applicable: c.436G>A p.Ala146Thr is missense, whereas BP1 is limited to the VCEP's specified truncating variants.	cspec
BP2	Not assessed	Not assessed: no qualifying phase or pathogenic-allele observation is documented, so the VCEP negative-point threshold cannot be evaluated.	cspec
BP3	N/A	Not applicable: the KRAS VCEP explicitly marks BP3 not applicable and identifies no known benign repetitive areas in RASopathy genes.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.909 exceeds the KRAS VCEP BP4 missense cutoff of <=0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point total is documented for this case.	cspec
BP6	N/A	Not applicable: the KRAS VCEP prohibits use of BP6 for this VCEP.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, intronic, or non-coding variants, whereas c.436G>A is missense p.(Ala146Thr).	cspec

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