KRAS c.292G>T, p.(Glu98Ter)

Reasoning

PM2_Supporting is met. The governing ClinGen RASopathy Expert Panel KRAS v2.3 rule requires the variant to be absent from controls (gnomAD). Direct queries found this variant absent from both gnomAD v2.1 and gnomAD v4.1. Its additional absence from gnomAD-Canada v1.0 is concordant. No frequency, ancestry-specific enrichment, or homozygote observation creates a threshold artifact.

Rule

The variant must be absent from controls (gnomAD); Supporting strength (ClinGen RASopathy Expert Panel KRAS v2.3).

Evidence considered

• The KRAS RASopathy VCEP v2.3 PM2 rule assigns Supporting strength when the variant is absent from controls (gnomAD).
• Direct variant queries reported NM_033360.4:c.292G>T / GRCh37 12-25378706-C-A absent from gnomAD v2.1 and GRCh38 chr12-25225772-C-A absent from gnomAD v4.1; gnomAD-Canada v1.0 also reported absence.

Sources

Reasoning

The KRAS RASopathy VCEP v2.3 spec directs that, because the RASopathy disease mechanism is gain-of-function, BP1 should be applied to any truncating variant (nonsense, frameshift, canonical splice-site, initiation codon, or whole-gene/multi-exon deletion) in genes without an established loss-of-function correlation to disease. NM_033360.4:c.292G>T produces p.(Glu98Ter), a nonsense/truncating variant. This same VCEP v2.3 spec independently marks PVS1 'Not Applicable' for KRAS, consistent with KRAS RASopathy pathogenicity being driven by gain-of-function/activating missense mechanisms rather than loss-of-function, supporting BP1 applicability here. OncoKB's variant-level annotation for this allele also characterizes its biological effect as likely loss-of-function, consistent with a benign-leaning truncating change under a GOF disease mechanism.

Rule

BP1 (VCEP KRAS v2.3): Truncating variant in a gene without established LOF-disease correlation, given RASopathy GOF mechanism.

Evidence considered

• cSpec (KRAS RASopathy VCEP v2.3) BP1 rule: 'Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant ... in genes without established LOF correlation to disease.'
• cSpec (KRAS RASopathy VCEP v2.3) marks PVS1 'Not Applicable' for KRAS, consistent with a GOF-only disease mechanism and absence of an established LOF-disease correlation for this gene within the spec.
• OncoKB variant page for KRAS E98* records biological-effect context as 'Likely Loss-of-function', consistent with this nonsense variant acting through loss rather than gain of function.

Still missing

• The VCEP BP1 rule text refers reviewers to supplemental gene-specific dosage-sensitivity material to confirm KRAS lacks an established LOF-disease correlation; that supplemental dosage table was not present in this case's VCEP materials bundle, so this determination relies on the spec's PVS1='Not Applicable' designation for KRAS as a proxy rather than direct dosage-sensitivity documentation.

Sources

Reasoning

PM1 in the KRAS RASopathy VCEP v2.3 spec is restricted to four critical, well-established functional domains: P-loop (aa 10-17), Switch I/SW1 (aa 25-40), Switch II/SW2 (aa 57-64), and the SAK region (aa 145-156), and is explicitly stated as not applicable to specific amino acid residues (which fall under PM5 instead). Residue 98 (Glu98) does not fall within any of these four domains, so PM1 is not met.

Rule

PM1 (VCEP KRAS v2.3): Applicable only to critical/well-established functional domains (P-loop 10-17, SW1 25-40, SW2 57-64, SAK 145-156).

Evidence considered

• cSpec (KRAS RASopathy VCEP v2.3) PM1 rule and the VCEP domain-alignment slide deck restrict PM1 to P-loop (10-17), SW1 (25-40), SW2 (57-64), and SAK (145-156); residue 98 falls outside all four ranges.

Sources

Reasoning

The governing ClinGen RASopathy Expert Panel KRAS v2.3 specification defines BA1 as gnomAD filtering allele frequency >=0.05% (Stand Alone). This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no total or ancestry-specific frequency can meet the BA1 threshold.

Rule

GnomAD filtering allele frequency >=0.05% (ClinGen RASopathy Expert Panel KRAS v2.3).

Evidence considered

• The KRAS RASopathy VCEP v2.3 BA1 rule requires a gnomAD filtering allele frequency of at least 0.05%.
• Direct variant queries reported NM_033360.4:c.292G>T / GRCh37 12-25378706-C-A absent from gnomAD v2.1 and GRCh38 chr12-25225772-C-A absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

The governing ClinGen RASopathy Expert Panel KRAS v2.3 specification defines BS1 as gnomAD filtering allele frequency >=0.025% (Strong). The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; it therefore cannot meet this threshold. Disease prevalence, autosomal-dominant inheritance, and penetrance need not be recalibrated because the applicable VCEP specification supplies the threshold.

Rule

GnomAD filtering allele frequency >=0.025% (ClinGen RASopathy Expert Panel KRAS v2.3).

Evidence considered

• The KRAS RASopathy VCEP v2.3 BS1 rule requires a gnomAD filtering allele frequency of at least 0.025%.
• Direct variant queries reported NM_033360.4:c.292G>T / GRCh37 12-25378706-C-A absent from gnomAD v2.1 and GRCh38 chr12-25225772-C-A absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

No affected proband with parental testing is documented for this variant; confirmed de novo occurrence cannot be established.

Rule

KRAS RASopathy VCEP PS2: 1 point = Moderate; 2 points = Strong; 4 points = Very Strong.

Evidence considered

• The KRAS RASopathy VCEP specification uses PS2 point-based strengths: 1 point (Moderate), 2 points (Strong), and 4 points (Very Strong). The supplied case evidence contains no germline proband, parental genotype, parentage, or phenotype data for NM_033360.4:c.292G>T.

Still missing

• Variant testing results for both biological parents, including confirmation of parentage, are needed.
• For each confirmed de novo proband, phenotype specificity and the RASopathy diagnosis must be documented to assign the VCEP point total.

Sources

Reasoning

The ClinGen RASopathy VCEP (cspec v2.3) makes PS3 applicable for KRAS, requiring one or more of the VCEP-approved functional assays (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) to reach Supporting (1 assay) or Moderate (2+ assays) strength. No results from any of these approved assays for this specific variant, NM_033360.4:c.292G>T (p.Glu98Ter), were found in the case bundle. OncoKB annotates a 'biological-effect context' of Likely Loss-of-function but an overall curated oncogenicity label of Likely Neutral for this variant; this is a curated database summary, not a description of a VCEP-approved wet-lab functional assay, is internally discordant, and does not specify assay methodology, controls, or replicate data, so it cannot be used to satisfy PS3. The two full-text literature papers retrieved for functional/OncoKB themes (PMID:28978093, PMID:34117033) were searched for this exact variant and neither mentions c.292G>T, p.Glu98Ter, or p.E98* anywhere in the text; they discuss KRAS/NRAS mutations in colorectal cancer cohorts generally without addressing this specific nonsense variant, so they cannot be grounded citations for PS3.

Evidence considered

• cspec (RASopathy VCEP v2.3) defines PS3 for KRAS as Supporting for one approved assay, Moderate for two or more different approved assays, drawn from the VCEP-approved functional studies list (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay, and gene-specific assays for other RASopathy genes)
• OncoKB entry for KRAS p.E98* reports biological-effect context 'Likely Loss-of-function' but curated oncogenicity label 'Likely Neutral' -- an internally discordant, non-assay-based curation that does not meet the VCEP's approved-assay requirement for PS3
• PMID:28978093 (Molecular characterization of circulating colorectal tumor cells) full text was searched for c.292G>T, Glu98Ter, and E98* and does not mention this variant
• PMID:34117033 (Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer) full text was searched for c.292G>T, Glu98Ter, and E98* and does not mention this variant

Still missing

• No RAS Activation Assay, MEK Activation Assay, or ERK Activation Assay data identified for p.(Glu98Ter)
• OncoKB curated classification is discordant (Likely Loss-of-function biological effect vs Likely Neutral oncogenicity label) and is not a described wet-lab assay, so it cannot substitute for an approved functional study
• No variant-specific full-text literature identified describing a validated functional assay for this variant

Sources

Reasoning

The KRAS RASopathy VCEP specification uses a point-based PS4 framework (Supporting at >=1 point, Moderate at >=3 points, Strong at >=5 points). The case bundle contains no germline RASopathy case series, phenotype-defined proband count, control comparison, or point assignment for p.(Glu98Ter). Somatic cancer observations cannot establish enrichment for the germline RASopathy indication.

Rule

ClinGen RASopathy Expert Panel KRAS v2.3: PS4 Supporting >=1 point; Moderate >=3 points; Strong >=5 points.

Evidence considered

• The governing ClinGen RASopathy Expert Panel KRAS v2.3 framework specifies PS4 at Supporting for >=1 point, Moderate for >=3 points, and Strong for >=5 points.
• COSMIC records three somatic cancer observations, which are not phenotype-defined germline RASopathy cases and do not provide a PS4 enrichment comparison.

Still missing

• Phenotype-defined germline RASopathy proband data for p.(Glu98Ter), including the VCEP point calculation and any case-control enrichment analysis, are required.

Sources

Reasoning

No proband occurrence with unavailable or untested parental samples is documented; assumed de novo occurrence cannot be established.

Rule

KRAS RASopathy VCEP PM6: 0.5 point = Supporting; 1 point = Moderate; 2 points = Strong.

Evidence considered

• The KRAS RASopathy VCEP specification uses PM6 point-based strengths: 0.5 point (Supporting), 1 point (Moderate), and 2 points (Strong). The supplied case evidence contains no germline proband or parental-testing status for this variant.

Still missing

• Document one or more affected probands carrying NM_033360.4:c.292G>T with parental samples unavailable or untested.
• For each occurrence, document phenotype specificity and the RASopathy diagnosis to assign VCEP de novo points.

Sources

Reasoning

No family segregation data or informative meioses are documented for this variant.

Rule

KRAS RASopathy VCEP PP1: >=3 informative meioses = Supporting; >=5 = Moderate; >=7 = Strong.

Evidence considered

• The KRAS RASopathy VCEP specification assigns PP1 at Supporting for at least 3 informative meioses, Moderate for at least 5, and Strong for at least 7. No pedigree or relative testing data are present in the supplied case evidence.

Still missing

• Provide pedigrees and genotype/phenotype results for informative relatives to count cosegregation meioses.
• At least 3, 5, or 7 informative meioses are required for Supporting, Moderate, or Strong evidence, respectively.

Sources

Reasoning

The applicable KRAS VCEP specification uses a phenotypically specified points-based BS2 rule (-4 points for Strong or -1 point for Supporting), rather than generic ACMG BS2. No evidence documents the variant in a healthy homozygous or heterozygous individual, an apparently unaffected family member, or any other observation that can be scored under that rule. The variant is absent from all queried population datasets and thus supplies no homozygote or carrier observation.

Rule

Points-based BS2: -4 points (Strong) or -1 point (Supporting), using RASopathy VCEP phenotypic specifications (ClinGen RASopathy Expert Panel KRAS v2.3).

Evidence considered

• The KRAS RASopathy VCEP v2.3 BS2 rule assigns Strong at -4 points and Supporting at -1 point based on phenotypic specifications.
• Direct variant queries reported the variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; no homozygote or healthy-carrier observation is available from these sources.

Still missing

• Phenotypically characterized healthy or apparently unaffected carrier observations, with the information needed to assign the VCEP BS2 point score, are unavailable.

Sources

Reasoning

No informative relative is documented in whom the variant fails to segregate with a relevant phenotype.

Rule

KRAS RASopathy VCEP BS4: one informative meiosis demonstrating non-segregation = Strong.

Evidence considered

• The KRAS RASopathy VCEP specification permits BS4 at Strong strength with one informative meiosis. The supplied case evidence contains no pedigree, relative genotype, or phenotype information.

Still missing

• Provide genotype and phenotype data for at least one informative meiosis demonstrating non-segregation, with phenotyping adequate for the relevant KRAS-associated condition.

Sources

Reasoning

No affected-proband observation, second pathogenic variant, phase determination, or phenotype information is provided to award the VCEP BP2 point-based evidence.

Rule

KRAS RASopathy VCEP v2.3 BP2: alternative molecular cause in the same gene with phenotype-consistent severity; Supporting ≥ -1 point, Moderate ≥ -2 points, Strong ≥ -4 points.

Evidence considered

• The KRAS RASopathy VCEP specifies BP2 as a point-based criterion for an alternative molecular cause of a RASopathy in the same gene, with phenotype consistent with expected severity; Supporting, Moderate, and Strong require at least -1, -2, and -4 points, respectively.
• The consolidated case bundle contains no germline affected-proband observation or co-occurring pathogenic/likely pathogenic KRAS variant, no cis/trans phase result, and no phenotype/severity data from which BP2 points can be assigned.

Still missing

• An affected-proband genotype showing a pathogenic or likely pathogenic alternative molecular cause in KRAS, with phase if relevant.
• Phenotype and severity information demonstrating consistency with the expected RASopathy severity for the alternative molecular cause.

Sources

Reasoning

The KRAS RASopathy VCEP specification applies BP5 by a point system (Supporting at >=-1 point, Moderate at >=-2 points, Strong at >=-4 points). No patient phenotype, alternate molecular diagnosis, or negative-point calculation is available in the bundle for p.(Glu98Ter).

Rule

ClinGen RASopathy Expert Panel KRAS v2.3: BP5 Supporting >=-1 point; Moderate >=-2 points; Strong >=-4 points.

Evidence considered

• The governing KRAS RASopathy VCEP specification sets BP5 thresholds at >=-1 point (Supporting), >=-2 points (Moderate), and >=-4 points (Strong).
• No individual-level alternate-diagnosis evidence or BP5 point total is provided for this variant.

Still missing

• A phenotype-documented individual with an independently established alternate molecular diagnosis and the corresponding VCEP negative-point calculation is required.

Sources