Variant classification summary

NM_004985.5:c.34G>C

KRAS · NP_004976.2:p.(Gly12Arg) · NM_004985.5

GRCh37: chr12:25398285 C>G · GRCh38: chr12:25245351 C>G

Gene: KRAS Transcript: NM_004985.5

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Gly12Arg)

gnomAD AF

0.0 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 Moderate: p.Gly12Arg lies within the approved KRAS P-loop domain at amino acids 10–17.

2

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1 controls.

3

PP3 Supporting: REVEL 0.821 exceeds the KRAS VCEP missense threshold of 0.7.

Final determination: Under the KRAS VCEP Version 2.3 framework, one Moderate criterion plus two Supporting criteria is not a listed pathogenic combination, and no benign rule is satisfied; therefore the 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: c.34G>C produces the missense change p.Gly12Arg, while the KRAS VCEP marks PVS1 not applicable.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: p.G12R is reported experimentally, but no previously established pathogenic alternate nucleotide change encoding the same amino-acid change was identified.	cspec PMID:22722830 PMID:32792368 vcep_alignment_with_pm1_domains_pptx
PS2	Not assessed	Not assessed: no proband-level de novo result or parental maternity and paternity confirmation is available for the required 1-, 2-, or 4-point PS2 assessment.	cspec
PS3	Not assessed	Not assessed: no exact G12R entry was found in the governing functional-studies table, and the available studies were not listed as approved KRAS assay instances.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22722830 PMID:32792368
PS4	Not assessed	Not assessed: no germline affected-versus-control counts, odds ratio with confidence interval, or qualifying multiple-unrelated-patient RASopathy evidence is available for the variant.	cspec PMID:22722830 PMID:28572459 PMID:24627688 PMID:32792368 gnomad_v2 gnomad_v4
PM1	Met	Met at Moderate: residue 12 lies within the VCEP-approved P-loop domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met at supporting: gnomAD v2.1 shows 0/249272 alleles and zero homozygotes, and gnomAD v4.1 reports absence.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the KRAS VCEP explicitly designates PM3 as not applicable for this RASopathy framework.	cspec
PM4	N/A	Not applicable: p.(Gly12Arg) is a missense substitution with no protein-length change, not an in-frame indel or stop-loss variant.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: zero same-residue comparator candidates were available, so neither the one-change Moderate nor two-change/five-proband Strong threshold was established.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo observation or parental-testing information is available for the VCEP's 0.5-, 1-, or 2-point PM6 thresholds.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP's at least 3, 5, or 7 meiosis thresholds can be evaluated.	cspec
PP2	N/A	Not applicable: the KRAS VCEP explicitly excludes PP2 because the missense z score is below 3.09.	cspec
PP3	Met	Met: REVEL 0.821 meets the KRAS VCEP PP3 missense threshold of >=0.7 at Supporting strength.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP explicitly excludes PP4 and directs phenotype-specific assessment to PS4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP states that PP5 is not for use for this VCEP.	cspec
BA1	Not met	Not met: gnomAD filtering allele frequency is 0.00000%, below the VCEP's 0.05% stand-alone threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD filtering allele frequency is 0.00000%, below the VCEP's 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no control homozygote or VCEP BS2 point evidence is available.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the KRAS VCEP explicitly marks BS3 not applicable, regardless of functional-study normal-readout thresholds.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected-family-member non-segregation result or informative meiosis is documented for the VCEP's one-meiosis BS4 threshold.	cspec
BP1	N/A	Not applicable: c.34G>C is a missense substitution, whereas the VCEP limits BP1 to truncating or other loss-of-function variants.	cspec
BP2	Not assessed	Not assessed: no documented alternate same-gene molecular cause or phase information is available to establish the VCEP's required BP2 point total.	cspec
BP3	N/A	Not applicable: p.(Gly12Arg) is a missense substitution, whereas BP3 is restricted to in-frame deletions or insertions in repetitive regions.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.821 exceeds the KRAS VCEP BP4 missense threshold of <=0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or qualifying discordant phenotype is documented, so the VCEP BP5 point total cannot be calculated.	cspec
BP6	N/A	Not applicable: the KRAS VCEP states that BP6 is not for use for this VCEP.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, qualifying intronic, or non-coding variants, whereas c.34G>C is missense.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.