Variant classification summary

NM_004985.5:c.183A>C

KRAS · NP_004976.2:p.(Gln61His) · NM_004985.5

GRCh37: chr12:25380275 T>G · GRCh38: chr12:25227341 T>G

Gene: KRAS Transcript: NM_004985.5

Final call

VUS

PS3 supporting PM1 moderate

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Gln61His)

gnomAD AF

3.979180925398316e-06 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 supporting—an approved RAS-activation assay showed a 5- to 6-fold increase in KRAS-GTP.

2

VUS: PM1 moderate—residue 61 lies within the approved SW2 domain (amino acids 57-64).

Final determination: Under the KRAS VCEP Version 2.3 framework, PS3 supporting plus PM1 moderate does not satisfy any pathogenic or benign combination rule, so the final call 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 KRAS VCEP explicitly marks PVS1 not applicable, and c.183A>C is a missense p.(Gln61His) variant.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the same p.Q61H amino-acid change is documented under the VCEP evidence reviewed.	cspec PMID:20147967 PMID:25705018
PS2	Not assessed	Not assessed: no documented proband-level de novo event or confirmed parental genotypes are available to determine the VCEP's required PS2 points.	cspec
PS3	Met	Met at Supporting: one approved RAS-activation assay showed KRAS-Q61H produced a 5- to 6-fold increase in KRAS-GTP over empty-vector cells.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:25705018
PS4	Not met	Not met: no qualifying germline RASopathy case-control comparison, OR >5.0 with CI excluding 1.0, or multiple unrelated RASopathy patients with this variant was documented.	cspec PMID:21610151 PMID:23619274
PM1	Met	Met at Moderate: residue 61 lies within the VCEP-approved SW2 functional domain spanning amino acids 57-64.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: gnomAD v2.1 all-comers contains 1 allele among 251,308 (AF 3.98×10⁻⁶), so the VCEP's complete-absence requirement is unmet.	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: PM4 covers in-frame indels or stop-loss variants, whereas c.183A>C is a missense substitution with no protein length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no different likely pathogenic amino-acid change at KRAS codon 61 with the VCEP-required support is documented.	cspec PMID:20147967 PMID:25705018
PM6	Not assessed	Not assessed: no presumed de novo proband and parental evidence are documented to determine the VCEP's 2-, 1-, or 0.5-point PM6 assignment.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so the VCEP's thresholds of at least 3, 5, or 7 cannot be evaluated.	cspec
PP2	N/A	Not applicable: the VCEP excludes PP2 because the gnomAD missense z score is below 3.09.	cspec
PP3	Not met	Not met: REVEL 0.644 is below the VCEP PP3 missense threshold of >= 0.7.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP excludes PP4 and directs phenotype-specific evidence to PS4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP states that PP5 is not for use.	cspec
BA1	Not met	Not met: the highest observed gnomAD v2.1 population AF was 0.00992%, below the VCEP's 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed gnomAD v2.1 population AF was 0.00992%, below the VCEP's 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but the VCEP does not define how available observations map to its −4 or −1 BS2 point options.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the KRAS VCEP explicitly designates BS3 as not applicable, and the approved RAS-activation assay is designated BS3_NA.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no unaffected carrier or informative non-segregating meiosis is documented to meet the VCEP's one-meiosis requirement.	cspec
BP1	N/A	Not applicable: BP1 is restricted to truncating variant types, whereas this variant is missense p.Gln61His.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans phase or allelic partner is available to establish the VCEP's required BP2 point total.	cspec
BP3	N/A	Not applicable: BP3 is VCEP-not-applicable and concerns benign repetitive-region in-frame indels, not the missense p.(Gln61His) substitution.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.644 exceeds the VCEP BP4 missense threshold of <= 0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant, qualifying phenotype, or VCEP BP5 point total is documented.	cspec
BP6	N/A	Not applicable: the KRAS VCEP states that BP6 is not for use.	cspec
BP7	N/A	Not applicable: c.183A>C is a missense variant, whereas VCEP BP7 covers synonymous, noncanonical intronic, or non-coding variants.	cspec

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