KRAS c.250A>G, p.(Ile84Val)

Reasoning

The ClinGen RASopathy VCEP KRAS v2.3 specification (CSPEC doc 643243114) pre-assigns BP4 for missense variants when REVEL <= 0.3. The local REVEL v1.3 lookup returns 0.294 for NM_033360.3:c.250A>G (p.Ile84Val), which satisfies REVEL <= 0.3. Per the group mandate, the VCEP pre-assigned code is applied directly. This is consistent with, and not contradicted by, the splice-impact path: SpliceAI max delta score 0.04 predicts no significant splice impact, supporting a benign computational-evidence direction; however, the criterion is met solely on the VCEP REVEL rule and the SpliceAI result is not double-counted as a second BP4 code. BayesDel was not used (no verified published threshold). BP4 met at Supporting strength.

Rule

For missense variants: REVEL <= 0.3.

Evidence considered

• REVEL score 0.294 (source: revel, local REVEL v1.3 lookup) satisfies VCEP KRAS v2.3 BP4 threshold REVEL <= 0.3 (threshold source: ClinGen RASopathy VCEP KRAS v2.3, cspec doc 643243114) - 0.294 <= 0.3, BP4 met at Supporting.
• SpliceAI max delta score 0.04 (source: spliceai) predicts no significant splice impact; consistent with BP4 but not counted as an independent code.
• BayesDel score -0.119893 (source: bayesdel) not applied: no verified published threshold available to this pipeline, treated as insufficiently calibrated.

Still missing

• BayesDel score (-0.119893) could not be applied because no verified published threshold is available to this pipeline; score treated as not_available (insufficiently calibrated).

Sources

Reasoning

Governing framework: ClinGen RASopathy VCEP (KRAS v2.3) defines PM2 (Supporting) as 'The variant must be absent from controls (gnomAD).' The variant is absent from gnomAD v2.1 (GRCh37) and gnomAD-Canada v1.0, but it IS present in gnomAD v4.1 (GRCh38) as a single exome allele in the South Asian population (AC=1/AN=91,076; total AC=1/AN=1,613,834; AF=6.196e-07; 0 homozygotes; genome AC/AN=0). Under a strict reading of the VCEP 'absent from controls' requirement, presence of the single v4.1 allele means PM2 is not met. This is a borderline database-version/threshold artifact: the variant was absent in gnomAD v2.1 (the version contemporaneous with the VCEP rule) and the sole v4.1 allele is exome-only (genome AN=0), raising the possibility of a sequencing artifact. Human review is recommended: if the single allele is confirmed as an artifact, the variant would be absent from controls and PM2 (Supporting) would be met. ClinVar submissions (SCV003471699, Labcorp) applied PM2 citing 'not present in population databases (gnomad no frequency)', but this reflects older gnomAD data and is not used here as evidence; the adjudication is based on current gnomAD v4.1 counts.

Rule

The variant must be absent from controls (gnomAD) (ClinGen RASopathy VCEP KRAS v2.3)

Evidence considered

• gnomad_v4: present, 1 allele total (SAS 1/91,076), AF 6.196e-07, 0 homozygotes, exome-only (genome AN=0)
• gnomad_v2: variant absent
• gnomad_canada: variant absent
• cspec: RASopathy VCEP v2.3 PM2 rule - variant must be absent from controls (gnomAD)

Still missing

• Confirm whether the single gnomAD v4.1 South Asian exome allele (12-25227274-T-C) is a sequencing artifact; if artifact-confirmed, PM2 (Supporting) becomes met.
• gnomAD v4.1 genome AC/AN = 0 and grpmax_faf = null in the scrape; population-restricted allele counts could not be further verified.
• VCEP 'absent from controls' is stricter than a low-frequency threshold; no frequency cutoff is given by the VCEP to rescue PM2 for a single observed allele.

Sources

Reasoning

PM4 is applicable in the governing ClinGen RASopathy VCEP KRAS v2.3 framework (applicability "Applicable"; Moderate rule: "No known repetitive areas in gene. Use as described."; instructions: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants."). The CSPEC confirms KRAS has no known repetitive areas, so the repeat-region restriction does not limit PM4 for this gene. However, the criterion requires an actual protein length change (in-frame deletion/insertion or stop-loss variant). NM_033360.3:c.250A>G is a single-nucleotide missense substitution changing codon 84 isoleucine to valine (p.Ile84Val); the Mutalyzer translation of the variant transcript shows an identical-length protein (189 aa, same terminal stop) with only the Ile->Val change at residue 84, i.e., no in-frame indel and no stop-loss. SpliceAI reports no significant splicing impact (max delta score = 0.04), providing no evidence of an exon-skipping or length-altering transcript consequence. Because no protein length change occurs, PM4 is not met.

Rule

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. (ClinGen RASopathy VCEP KRAS v2.3, PM4 Moderate: "No known repetitive areas in gene. Use as described.")

Evidence considered

• cspec: PM4 applicability "Applicable"; rule "No known repetitive areas in gene. Use as described."; instructions "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants."
• prefetch normalization (Mutalyzer): variant protein translation shows Ile84Val with identical protein length (189 aa, unchanged stop) - no length change
• spliceai: max delta score 0.04 - no predicted splicing/length-altering consequence

Sources

Reasoning

Governing framework is the ClinGen RASopathy Expert Panel VCEP specification for KRAS v2.3 (CSPEC doc 643243114), which pre-assigns PP3 for missense variants only when REVEL >= 0.7 and requires that any predicted splicing impact match the (gain-of-function) disease mechanism. REVEL score for NM_033360.3:c.250A>G is 0.294, well below the 0.7 threshold, so the missense in-silico path does not meet PP3. On the splice-impact path, SpliceAI reports max delta score 0.04 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.04, DS_DL 0.04) with all four delta scores <= 0.04, i.e. no significant splice impact predicted, so no splice-altering outcome exists that could match the disease mechanism. BayesDel score (-0.119893) was considered but is treated as insufficiently calibrated because no verified published threshold is available to this pipeline, so it cannot support PP3. PP3 is therefore not met on either sub-path.

Rule

For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.

Evidence considered

• REVEL score 0.294 (source: revel, local REVEL v1.3 lookup) compared against VCEP KRAS v2.3 PP3 threshold REVEL >= 0.7 (threshold source: ClinGen RASopathy VCEP KRAS v2.3, cspec doc 643243114) - 0.294 < 0.7, PP3 not met on missense path.
• SpliceAI max delta score 0.04 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.04, DS_DL 0.04; source: spliceai, SpliceAI Lookup for NM_033360.3:c.250A>G) - no significant splice impact predicted, so no splice outcome matches the gain-of-function RASopathy mechanism; PP3 not met on splice path.
• BayesDel score -0.119893 (source: bayesdel) not applied: no verified published threshold available to this pipeline, treated as insufficiently calibrated.

Still missing

• BayesDel score (-0.119893) could not be applied because no verified published threshold is available to this pipeline; score treated as not_available (insufficiently calibrated).

Sources

Reasoning

PP5 requires an exact-variant ClinVar expert-panel (expert panel) classification of Pathogenic/Likely pathogenic. The governing RASopathy VCEP v2.3 marks PP5 Not Applicable, and the global PP5 policy applies it only when a ClinVar expert-panel classification exists (ordinary laboratory submissions and aggregate labels never trigger PP5). ClinVar VCV001318518 has expert_panel_submissions = 0 (expert_panels = {}), review_stars = 2, and a combined classification of Uncertain significance from two clinical-testing laboratories (GeneDx, Labcorp), neither of which is an expert panel (is_expert_panel = false). No expert-panel Pathogenic/Likely pathogenic classification exists for this exact variant, so PP5 is not met.

Rule

Global PP5 policy: exact-variant ClinVar expert-panel classification (Pathogenic/Likely pathogenic) required; RASopathy VCEP v2.3 marks PP5 Not Applicable and is overridden only when such an expert-panel classification exists

Evidence considered

• CSPEC RASopathy VCEP v2.3 rule payload: PP5 applicability = Not Applicable
• ClinVar VCV001318518: classification Uncertain significance, review_stars 2, expert_panels {}, expert_panel_submissions 0; submissions SCV002007287 (GeneDx) and SCV003471699 (Labcorp) both is_expert_panel = false, both Uncertain significance

Sources

Reasoning

Governing framework: ClinGen RASopathy VCEP (KRAS v2.3, CSPEC doc 643243114) defines BA1 as gnomAD filtering allele frequency >= 0.05% (Stand Alone). The variant is present in gnomAD v4.1 at total AF = 6.196e-07 (0.00006%, 1/1,613,834 alleles) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The highest observed population frequency is South Asian (AF = 1.098e-05, 0.00110%, 1/91,076 alleles), still ~45x below the 0.05% BA1 threshold. Total AF is ~800x below threshold. BA1 is not met regardless of whether total AF or the highest subpopulation AF is used; no population-frequency threshold artifact applies.

Rule

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

Evidence considered

• gnomad_v4: total AF 6.196e-07 (0.00006%), 1/1,613,834 alleles; best subpopulation South Asian AF 1.098e-05 (0.00110%)
• gnomad_v2: variant absent
• cspec: RASopathy VCEP v2.3 BA1 rule threshold 0.05%

Still missing

• gnomAD v4.1 scrape does not expose the legacy gnomAD 'filtering allele frequency' metric; total AF and population-specific AF were used as proxies. Impact negligible given AF is 2-3 orders of magnitude below the 0.05% threshold.

Sources

Reasoning

Governing framework: ClinGen RASopathy VCEP (KRAS v2.3) defines BS1 as gnomAD filtering allele frequency >= 0.025% (Strong). Observed gnomAD v4.1 total AF = 6.196e-07 (0.00006%) and highest subpopulation AF (South Asian) = 1.098e-05 (0.00110%) are both far below the 0.025% threshold (total AF ~400x below). Variant is absent from gnomAD v2.1 and gnomAD-Canada. BS1 is not met. Disease prevalence/penetrance considerations for RASopathy (autosomal dominant, high penetrance with variable expressivity) do not alter this outcome because the VCEP has already encoded these into the 0.025% threshold, which the observed frequency does not approach.

Rule

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

Evidence considered

• gnomad_v4: total AF 6.196e-07 (0.00006%); highest subpopulation (SAS) AF 1.098e-05 (0.00110%)
• gnomad_v2: variant absent
• cspec: RASopathy VCEP v2.3 BS1 rule threshold 0.025%

Still missing

• Legacy gnomAD 'filtering allele frequency' metric not exposed in the v4.1 scrape; total/population AF used as proxy. Negligible impact given ~400x headroom below threshold.

Sources

Reasoning

Governing framework: ClinGen RASopathy VCEP (KRAS v2.3) implements BS2 as a points-based rule (-4 points = Strong, -1 point = Supporting), replacing the generic ACMG 'observed in healthy adult' formulation; the underlying point scheme is not fully reconstructible from the case bundle. Independent of the point scheme, the population data contain zero homozygous observations in any gnomAD v4.1 population (including the single-carrier South Asian subpopulation) and no healthy-adult/homozygous observations in gnomAD v2.1 or gnomAD-Canada. The single heterozygous carrier (1/1,613,834 alleles, gnomAD v4.1) is not BS2 evidence: RASopathy is autosomal dominant with high but variable penetrance, and gnomAD is a general-population cohort without confirmed unaffected phenotype. No available data satisfies any BS2 threshold; BS2 is not met.

Rule

Points-based: -4 points (Strong), -1 point (Supporting) (ClinGen RASopathy VCEP KRAS v2.3)

Evidence considered

• gnomad_v4: 0 homozygotes across all populations (total AN 1,613,834)
• gnomad_v2: variant absent
• gnomad_canada: variant absent
• cspec: RASopathy VCEP v2.3 BS2 points rule

Still missing

• RASopathy VCEP BS2 point-scheme details (-4/-1 points) could not be independently applied from the bundle; adjudication rests on absence of homozygous and healthy-adult observations, which fails any BS2 formulation.

Sources

Reasoning

BP6 requires an exact-variant ClinVar expert-panel (expert panel) classification of Benign/Likely benign. The governing RASopathy VCEP v2.3 marks BP6 Not Applicable, and the global BP6 policy applies it only when a ClinVar expert-panel classification exists (ordinary laboratory submissions and aggregate labels never trigger BP6). ClinVar VCV001318518 has expert_panel_submissions = 0 (expert_panels = {}), review_stars = 2, and a combined classification of Uncertain significance from two clinical-testing laboratories (GeneDx, Labcorp), neither of which is an expert panel (is_expert_panel = false). No expert-panel Benign/Likely benign classification exists for this exact variant, so BP6 is not met.

Rule

Global BP6 policy: exact-variant ClinVar expert-panel classification (Benign/Likely benign) required; RASopathy VCEP v2.3 marks BP6 Not Applicable and is overridden only when such an expert-panel classification exists

Evidence considered

• CSPEC RASopathy VCEP v2.3 rule payload: BP6 applicability = Not Applicable
• ClinVar VCV001318518: classification Uncertain significance, review_stars 2, expert_panels {}, expert_panel_submissions 0; submissions SCV002007287 (GeneDx) and SCV003471699 (Labcorp) both is_expert_panel = false, both Uncertain significance

Sources

Reasoning

PS1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No proband observation of NM_033360.3:c.250A>G (p.Ile84Val) with confirmed de novo origin is present anywhere in the case bundle. There is no parental testing result, no paternity/maternity confirmation, and no phenotype-consistency assessment tied to a de novo occurrence. The governing ClinGen RASopathy VCEP (KRAS v2.3) PS2 rule is point-based (4 points = Very Strong, 2 points = Strong, 1 point = Moderate, per the SVI de novo criteria proposal referenced by the CSPEC entry); with zero de novo observations, zero points can be assigned and the criterion cannot be evaluated. ClinVar record 1318518 (two germline VUS submissions) was reviewed and contains no de novo assertion; the ClinVar VUS classification is not evidence for any criterion.

Evidence considered

• ClinGen RASopathy VCEP KRAS v2.3 CSPEC rule: PS2 point-based (4/2/1 points for Very Strong/Strong/Moderate) - no points applicable with no de novo observation
• ClinVar record 1318518 (VCV001318518): 2 germline submissions (GeneDx, Labcorp), both Uncertain significance, no criteria or de novo/parental data reported
• PMID:28492532 full text searched: methodology paper (Sherloc), no variant-specific or proband data

Still missing

• No proband carrying the variant with a documented de novo occurrence
• No parental testing results demonstrating both biological parents are negative for the variant
• No paternity/maternity confirmation
• No phenotype consistency assessment for a de novo occurrence in the proband

Sources

Reasoning

Governing framework: ClinGen RASopathy VCEP (KRAS) v2.3 (cspec doc 643243114). PS3 is applicable, but the VCEP strength calibration caps it: Supporting = one approved assay, Moderate = two or more different approved assays (default Pathogenic Strong from generic ACMG is not available under this framework). Approved assays for KRAS (SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx) are pathway-specific RAS Activation, MEK Activation, and ERK Activation assays (assay-validation PMIDs for KRAS RAS activation: 20949621, 23059812). No variant-specific functional study of KRAS p.Ile84Val (c.250A>G) from any approved assay (or any functional assay at all) is present in this case: OncoKB classifies KRAS I84V as 'Unknown Oncogenic Effect' and explicitly states no variant-specific functional evidence has been reviewed (no citations); COSMIC has no somatic report of the variant; Cancer Hotspots is negative; and the only publication in the case (PMID 28492532, Sherloc methods paper, retrieved via ClinVar submission SCV003471699) contains no mention of KRAS, I84V, or functional assays in its full text. Evidence is therefore insufficient to apply PS3 at any strength; the criterion is not assessed, with the gap being the absence of a VCEP-approved assay result for this exact variant (>=1 approved assay for Supporting; >=2 different approved assays for Moderate). PS3 is not inferred from ClinVar VUS classifications or from any other source's final classification.

Rule

RASopathy VCEP v2.3 PS3: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.' Strength: Supporting - 'One approved assay.'; Moderate - 'Two or more different approved assays.'; Strong/Stand Alone - Not applicable.

Evidence considered

• cspec: RASopathy VCEP v2.3 PS3 rule - applicable; Supporting = one approved assay; Moderate = two or more different approved assays; Strong/Stand Alone not applicable.
• vcep_svi_rasopathy_vcep_v2_approved_functional_studies: Defines approved assays (RAS/MEK/ERK activation, pathway-specific for KRAS) and per-gene assay-validation PMIDs (KRAS RAS activation: 20949621, 23059812); contains no entry indicating I84V was tested.
• oncokb: KRAS I84V = Unknown Oncogenic Effect; is_variant_specific = false; not_reviewed = true; no variant-specific functional evidence and no citation PMIDs returned.
• PMID:28492532: Sherloc methods paper (Nykamp et al., Genet Med 2017); full text reviewed - zero occurrences of KRAS/Ile84/functional/assay; provides no variant-specific functional data.
• cosmic/hotspots (scanned): variant absent from COSMIC and not a statistically significant cancer hotspot - no functional/somatic context available.

Still missing

• No functional study of KRAS p.Ile84Val (c.250A>G) using a VCEP-approved assay (RAS Activation, MEK Activation, or ERK Activation) is available in the case evidence; PS3 Supporting requires >=1 approved assay and Moderate requires >=2 different approved assays demonstrating a damaging effect on RAS/MAPK pathway function.

Sources

Reasoning

PS4 (prevalence in affected individuals / case-control enrichment) is governed by the ClinGen RASopathy VCEP v2.3 point rule (>=1 point Supporting, >=3 Moderate, >=5 Strong), which requires case-level or case-control enrichment data. No such data exists in this case bundle: the only literature lead (PMID:28492532, Sherloc) is a generic ACMG/AMP refinement methods paper whose full text contains no mention of KRAS, c.250A>G, p.Ile84Val, or any case-control cohort; no proband counts or odds ratios are reported anywhere. ClinVar (VCV001318518) contains two laboratory submissions both classified Uncertain significance with no case-level counts, and gnomAD v4.1 shows a single allele (AF 6.196e-07, 1/1,613,834) in controls, which provides no enrichment signal. With no case-control study or proband cohort data available, PS4 cannot be scored; the criterion is returned not_assessed pending such evidence.

Rule

ClinGen RASopathy Expert Panel v2.3 (CSPEC doc 643243114): PS4 >=5 points = Strong, >=3 points = Moderate, >=1 point = Supporting (point-based case-control enrichment rule)

Evidence considered

• CSPEC RASopathy VCEP v2.3 rule payload: PS4 >=1 point Supporting / >=3 Moderate / >=5 Strong (point-based case-control enrichment rule)
• ClinVar VCV001318518: classification Uncertain significance, review_stars 2, 2 laboratory submissions (GeneDx SCV002007287, Labcorp SCV003471699), both VUS, no case-level data
• gnomAD v4.1: AF 6.196e-07 (1/1,613,834 alleles), 0 homozygotes; absent from gnomAD v2.1 and gnomAD-Canada (control-frequency context only, no enrichment signal)
• PMID:28492532 full text reviewed: no mention of KRAS, c.250A>G, p.Ile84Val, or case-control enrichment

Still missing

• No case-control or cohort study for KRAS c.250A>G (p.Ile84Val) reporting variant counts in affected individuals versus controls
• No proband counts or odds ratio/effect size data; ClinVar submissions carry no case-level counts
• PMID:28492532 was flagged as a PS4 candidate lead but contains no variant-specific or case-control content and must not be used as PS4 evidence

Sources

Reasoning

PM1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

PM5 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No de novo occurrence of the variant is reported with or without parental confirmation, so the VCEP PM6 point rule (2 points = Strong, 1 point = Moderate, 0.5 points = Supporting for assumed de novo without parental confirmation) cannot be scored. No case report, cohort, or ClinVar submission in the bundle asserts a de novo origin for c.250A>G.

Evidence considered

• ClinGen RASopathy VCEP KRAS v2.3 CSPEC rule: PM6 point-based (2/1/0.5 points for Strong/Moderate/Supporting) - no points applicable with no de novo observation
• ClinVar record 1318518: no de novo assertion in either submission
• PMID:28492532 full text searched: no variant-specific case data

Still missing

• No de novo observation even without parental confirmation
• No case report or cohort documenting this exact variant as de novo in a proband
• No maternal/paternal age or recurrence data relevant to de novo occurrence

Sources

Reasoning

No segregation data exist: no affected relatives were tested and there are zero informative meioses reported for this variant. The VCEP PP1 rule requires >=3 informative meioses for Supporting, >=5 for Moderate, and >=7 for Strong; the available evidence does not reach the threshold for any strength. No family history or co-segregation information is present in the case bundle, ClinVar record 1318518, or the available literature.

Evidence considered

• ClinGen RASopathy VCEP KRAS v2.3 CSPEC rule: PP1 requires >=3 (Supporting) / >=5 (Moderate) / >=7 (Strong) informative meioses - none available
• ClinVar record 1318518: no segregation assertions
• PMID:28492532 full text searched: no segregation data

Still missing

• No affected family members tested for the variant
• Zero informative meioses available
• No family history information in the case bundle

Sources

Reasoning

PP2 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No non-segregation observation is available: there are no affected individuals reported who were tested and found NOT to carry the variant. The VCEP BS4 rule is notably permissive (one informative meiosis demonstrating non-segregation is sufficient for Strong), but even a single such observation is absent from the case bundle, ClinVar record 1318518, and the available literature.

Evidence considered

• ClinGen RASopathy VCEP KRAS v2.3 CSPEC rule: BS4 Strong requires only one informative meiosis (non-segregation) - none available
• ClinVar record 1318518: no segregation or non-segregation data
• PMID:28492532 full text searched: no non-segregation observations

Still missing

• No affected family members tested and found negative for the variant (non-segregation)
• No informative meiosis demonstrating absence of the variant in an affected individual

Sources

Reasoning

BP1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

Under the governing ClinGen RASopathy VCEP v2.3, BP2 is a points-based benign-observation rule (Supporting at >= -1 point, Moderate at >= -2 points, Strong at >= -4 points) rather than the generic ACMG trans/cis phrasing. The consolidated case-evidence bundle contains no proband-level or family observations of any kind for this variant: no trans/cis phase information, no co-occurrence with a pathogenic variant, no unaffected-carrier or unaffected-relative observations, and no segregation data. ClinVar (variation ID 1318518) holds two germline Uncertain-significance submissions (GeneDx SCV002007287; Labcorp SCV003471699) with no phase, family, or phenotype detail. With zero observations, no points can be accrued and BP2 cannot be met at any strength; the evidence required to score the rule is absent rather than merely below threshold. The only available publication (PMID:28492532, Sherloc) is a criteria-refinement methods paper that does not mention c.250A>G or p.Ile84Val, so it supplies no BP2-relevant observation.

Rule

VCEP BP2: >= -1 point Supporting; >= -2 points Moderate; >= -4 points Strong (0 points accrued - no benign-observation data)

Evidence considered

• ClinGen RASopathy VCEP v2.3 (CSPEC doc 643243114): BP2 points rule thresholds (Supporting >= -1, Moderate >= -2, Strong >= -4 points); no qualifying observation data exist to score
• ClinVar variation 1318518: 2 germline Uncertain-significance submissions (SCV002007287 GeneDx; SCV003471699 Labcorp), both 'criteria provided, single submitter', conditions RASopathy/not provided; no phase, family, or co-occurrence information reported

Still missing

• No proband or family observation data in the case bundle: trans/cis phase of c.250A>G with any second KRAS variant is unknown
• No co-occurrence observations (variant observed in trans with a pathogenic variant, or in cis with a pathogenic variant) are documented
• No unaffected-carrier / unaffected-relative observations available to accrue VCEP BP2 points; the VCEP point-assignment table is not included in the bundle, so even partial observations could not be fully scored without it

Sources

Reasoning

BP5 (variant observed in a case with an alternate molecular basis for disease) is governed by the ClinGen RASopathy VCEP v2.3 Bayesian point rule (>= -1 point Supporting, >= -2 Moderate, >= -4 Strong). The point system requires proband-level observations documenting an alternate molecular explanation for the phenotype in a carrier of this variant. No such data exists in the case bundle: no proband case reports, no alternate-cause annotations in either ClinVar submission (both VUS, clinical testing only), and no relevant literature. With no case-level evidence of an alternate molecular basis, BP5 cannot be scored and is returned not_assessed.

Rule

ClinGen RASopathy Expert Panel v2.3 (CSPEC doc 643243114): BP5 >= -1 point = Supporting, >= -2 points = Moderate, >= -4 points = Strong (point-based alternate-molecular-basis rule)

Evidence considered

• CSPEC RASopathy VCEP v2.3 rule payload: BP5 >= -1 point Supporting / >= -2 Moderate / >= -4 Strong (Bayesian point rule)
• ClinVar VCV001318518: 2 submissions, both Uncertain significance, clinical testing only, no alternate molecular basis annotations

Still missing

• No proband-level evidence that an alternate molecular basis for disease was identified in any individual carrying KRAS c.250A>G
• No ClinVar submission or publication provides case annotations (e.g., second variant, alternative diagnosis) relevant to the BP5 point rule

Sources