Variant classification summary

NM_004985.5:c.38G>A

KRAS · NP_004976.2:p.(Gly13Asp) · NM_004985.5

GRCh37: chr12:25398281 C>T · GRCh38: chr12:25245347 C>T

Gene: KRAS Transcript: NM_004985.5

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM5 moderate PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Gly13Asp)

gnomAD AF

3.100206101701641e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: KRAS G13D showed substantially increased nucleotide exchange and reduced intrinsic GTP hydrolysis versus wild type.

2

PM1 moderate: Gly13 lies within the VCEP-approved P-loop domain spanning residues 10-17.

3

PM5 moderate: the VCEP table lists pathogenic KRAS G13C, a different pathogenic change at codon 13.

4

PP3 supporting: REVEL 0.832 exceeds the VCEP missense threshold of 0.7.

Final determination: Under Rule14 of the ClinGen RASopathy Expert Panel KRAS v2.3 framework, two moderate pathogenic criteria (PM1 and PM5) together with at least two supporting pathogenic criteria (PS3 and PP3) produce a Likely Pathogenic call.

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 explicitly marks PVS1 not applicable, and c.38G>A is a missense p.(Gly13Asp) substitution.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no different-nucleotide pathogenic comparator producing p.Gly13Asp was established, although the VCEP table lists the exact KRAS G13D variant as pathogenic.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies vcep_alignment_with_pm1_domains_pptx
PS2	Not assessed	Not assessed: no confirmed parental testing or VCEP PS2 point assignment is documented for a proband.	PMID:22722830
PS3	Met	Met at Supporting: KRAS G13D showed 14-fold faster GDP exchange, 9-fold faster GTP exchange, and approximately 7-fold lower intrinsic GTP hydrolysis than wild type.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:26037647
PS4	Not met	Not met: no variant-specific case-control comparison or VCEP PS4 point total is established, despite two somatic KRAS G13D RALD cases.	cspec PMID:21063026 PMID:15696205 PMID:19681119 gnomad_v4
PM1	Met	Met at moderate strength: Gly13 lies within the VCEP-approved P-loop critical domain spanning residues 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: the variant is present in gnomAD v3.1 non-cancer genomes at 3/147,924 alleles and gnomAD v4.1 at 5/1,612,796.	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: c.38G>A is a missense substitution with p.(Gly13Asp), not an insertion or deletion causing a protein-length change.	cspec pvs1_variant_assessment
PM5	Met	Met at moderate strength: the VCEP functional-study table lists KRAS G13C as pathogenic, a different pathogenic residue change at codon 13.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM6	Not assessed	Not assessed: no de novo observation without parental testing or VCEP PM6 point assignment is documented for this variant.	PMID:22722830
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP thresholds of 3, 5, or 7 can be evaluated.	PMID:22722830
PP2	N/A	Not applicable: the KRAS VCEP explicitly excludes PP2 because its missense z-score requirement is not met.	cspec
PP3	Met	Met: REVEL score 0.832 meets the KRAS VCEP PP3 missense threshold of >=0.7.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP explicitly excludes PP4 and directs relevant phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP prohibits PP5, regardless of pathogenic ClinVar or literature assertions.	cspec clinvar
BA1	Not met	Not met: the highest observed frequency was 0.00463% in gnomAD v3.1 non-cancer genomes, below the VCEP's 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed frequency was 0.00463% in gnomAD v3.1 non-cancer genomes, below the VCEP's 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: all queried gnomAD datasets show zero homozygotes, but the VCEP's BS2 point mapping is not specified.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the KRAS RASopathy VCEP v2.3 explicitly designates BS3 as not applicable, and the available G13D assays show damaging functional changes.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:26037647
BS4	Not assessed	Not assessed: no informative meiosis demonstrating non-segregation is documented, despite the VCEP requirement for one.	PMID:22722830
BP1	N/A	Not applicable: BP1 is restricted to specified truncating variants, whereas this case is the missense substitution p.Gly13Asp.	cspec
BP2	Not assessed	Not assessed: no cis/trans observation or BP2 point assignment is available to evaluate the VCEP’s ≥ (-1) Point supporting threshold.	cspec
BP3	N/A	Not applicable: the KRAS VCEP explicitly marks BP3 not applicable for this interpretation.	cspec
BP4	Not met	Not met: REVEL score 0.832 exceeds the KRAS VCEP BP4 missense threshold of <=0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point assignment is documented for this case.	cspec
BP6	N/A	Not applicable: the KRAS VCEP prohibits BP6 for this framework.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, qualifying intronic, or non-coding variants, whereas c.38G>A is an exonic missense change.	cspec

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