RNF43 c.662G>A, p.(Arg221Gln)

Reasoning

PP5 is applied only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar VCV001169480 (NM_017763.6(RNF43):c.662G>A, p.Arg221Gln) contains no expert-panel submission (expert_panels empty; all 8 submitters are clinical laboratories with single-submitter review status; record is 2-star), and the aggregate classification is Benign, not Pathogenic/Likely pathogenic. No reputable-source pathogenic assertion for this exact variant exists in the evidence set, so PP5 is not met.

Rule

PP5 policy for this pipeline: apply at supporting strength only for an exact-variant ClinVar expert-panel (3-star) classification of Pathogenic/Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5.

Evidence considered

• ClinVar VCV001169480 shows no expert-panel participation (expert_panels: none; submitters are GeneDx, Ambry, Labcorp (Invitae), Amsterdam UMC, Academic Medical Center Amsterdam, Breakthrough Genomics, Rigshospitalet Copenhagen, and Sinai Health System, all classified as clinical laboratories).
• The aggregate ClinVar classification for the exact variant is Benign (criteria provided, multiple submitters, no conflicts), which is not a Pathogenic/Likely pathogenic expert-panel assertion and therefore cannot trigger PP5.
• No variant-specific literature asserting pathogenicity for c.662G>A was retrieved; the framework paper (PMID:25741868) does not mention this variant.

Still missing

• None: the expert-panel trigger condition for PP5 is definitively absent for this variant.

Sources

Reasoning

BP6 is applied only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign. Although ClinVar VCV001169480 is classified Benign by 8 clinical laboratories (2-star, criteria provided, multiple submitters, no conflicts), none of these submissions is an expert-panel assertion (expert_panels empty), and policy requires that ordinary laboratory submissions and aggregate ClinVar labels never trigger BP6. BP6 is therefore not met.

Rule

BP6 policy for this pipeline: apply at supporting strength only for an exact-variant ClinVar expert-panel (3-star) classification of Benign/Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6.

Evidence considered

• ClinVar VCV001169480 aggregate classification is Benign from 8 clinical laboratory submissions with no expert-panel participation and 2 review stars; this is a non-expert aggregate label.
• Under the governing BP6 policy, ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6 regardless of the Benign direction of the label; a ClinGen VCEP/expert-panel benign classification would be required and none exists.

Still missing

• None: the expert-panel trigger condition for BP6 is definitively absent; the non-expert aggregate Benign label must not be counted as BP6 evidence.

Sources

Reasoning

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

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PS2 (confirmed de novo, maternity and paternity confirmed) cannot be evaluated because the case bundle contains no patient-level data whatsoever: there is no proband clinical/phenotype record, no parental testing result, and no genotype data for the biological parents of any carrier. The only ClinVar record for NM_017763.6:c.662G>A (VCV001169480; 8 laboratories, all Benign, germline origin) carries no de novo or parental-genotype observations in any submission (evidence_signals empty for all 9 SCVs). Literature triage surfaced no segregation/de novo case reports for this variant; the only full-text-extracted paper, PMID:25741868 (ACMG/AMP 2015 standards), is the generic framework document and per paper_extracts.json contains no mention of RNF43, c.662G>A, or p.(Arg221Gln) and no variant-specific observations. Governing framework is generic ACMG/AMP 2015 (no ClinGen CSPEC/VCEP exists for RNF43; cspec found=false, final_classification_framework found=false). With no proband or parental evidence, PS2 is not assessed rather than met or not_met.

Rule

ACMG/AMP 2015 (PMID:25741868) PS2: de novo variant in a proband with the phenotype and no family history, with maternity and paternity confirmed

Evidence considered

• Case bundle contains no proband, phenotype, parental-testing, or family-history section; searches of the full bundle for proband/parent/de novo/segregation/pedigree terms returned no patient-level content
• ClinVar audit (prefetch.json submission_audit, 9 SCVs): every submission for VCV001169480 has empty evidence_signals and none reports a de novo observation or parental genotypes; all 8 clinical laboratories assert Benign
• paper_extracts.json PMID:25741868: ACMG/AMP 2015 standards define PS2 (confirmed de novo) but report no RNF43/c.662G>A/p.(Arg221Gln) data; no segregation or case-observation content
• Generic ACMG/AMP 2015 fallback applies because no RNF43 ClinGen CSPEC/VCEP was found (vcep_materials.json, review_manifest.json gene_vcep_dir null)

Still missing

• No proband clinical record or phenotype in the case bundle; required to establish that a de novo occurrence is even being evaluated
• No parental testing data (both parents' genotypes) and no confirmation of maternity/paternity for any reported carrier
• No variant-specific literature reporting a confirmed de novo occurrence of c.662G>A in RNF43

Sources

Reasoning

No ClinGen CSPEC/VCEP governs RNF43 (vcep_materials.json: cspec not found, framework_complete=false, precedence_rank=3), so generic ACMG/AMP 2015 (Richards et al., PMID:25741868) applies. PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect on protein function or splicing for the variant under evaluation. No such variant-specific evidence was retrieved for NM_017763.6:c.662G>A (p.Arg221Gln): OncoKB returned 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence and no citations; the only full-text paper in the case (PMID:25741868) is the ACMG framework document itself and does not mention RNF43, c.662G>A, or p.(R221Q); COSMIC (COSV68457520) records only somatic occurrence (n=3), which is not functional assay evidence; and the RNF43 gene-context functional literature present in the bundle (serrated-polyposis cohorts; C. elegans plr-1 loss-of-function modeling) concerns other/truncating alleles (e.g., p.Gln636Ter) and gene-level mechanism, not the functional effect of p.Arg221Gln. The positive damaging-effect premise of PS3 therefore cannot be established from any retrieved source.

Rule

PS3 (generic ACMG/AMP 2015, PMID:25741868): well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product

Evidence considered

• Governing framework: RNF43 has no ClinGen CSPEC/VCEP entry (vcep_materials.json: 'no cspec url available', framework_complete=false, precedence_rank=3, scoring_model 'ACMG/AMP 2015'); generic ACMG/AMP 2015 fallback (Richards et al. 2015, PMID:25741868) defines PS3 as 'well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'.
• OncoKB variant page for RNF43 R221Q (source registry key 'oncokb') returned classification 'Unknown Oncogenic Effect' with the explicit statement that no variant-specific reviewed functional evidence was identified (is_variant_specific=false, not_reviewed=true, citations_pmids empty); unusable as functional evidence for PS3 or BS3.
• paper_extracts.json (source registry key 'PMID:25741868', the only full-text paper mapped in fulltext_map.json): no mention of RNF43, c.662G>A, or p.(R221Q); no functional assay data; variant_mentioned=false; extract finding used directly as the selectively-read record for this paper.
• ClinVar record (source registry key 'clinvar', variation ID 1169480; Benign, 8 clinical laboratories, review status 'criteria provided, single submitter') is an aggregate laboratory classification, not a functional assay result; per adjudication rules it was not used to infer or support PS3 or BS3.
• COSMIC entry COSV68457520 (source registry key 'cosmic') reports somatic occurrence count n=3; recurrence/occurrence data are not functional assay evidence and were not used for PS3/BS3.
• RNF43 gene-context literature present in the case bundle (serrated polyposis/CRC cohort studies; C. elegans plr-1 loss-of-function modeling of the different allele NM_001305545.1:c.1906C>T p.Gln636Ter) addresses gene mechanism or other alleles and does not test c.662G>A/p.Arg221Gln, so none qualifies as PS3 evidence.
• literature_pass.json triage surfaced no functional-assay paper for this variant; the four registry PMIDs are two PDQ review summaries (26389258, 26389505), the ACMG framework paper (25741868), and the Sherloc framework paper (28492532) - none is a variant-specific functional study.
• In silico outputs present in the case (SpliceAI, REVEL 0.092, BayesDel) are predictor scores relevant to splicing/PP3-BP4-type reasoning, not well-established functional studies; not used for PS3/BS3.

Still missing

• No well-established in vitro or in vivo functional study of RNF43 p.(Arg221Gln)/c.662G>A was retrieved (e.g., Wnt/beta-catenin TOPflash reporter, Frizzled ubiquitination/degradation, or cell-growth assay); a validated, controlled assay result showing a damaging effect on RNF43 function would be required before PS3 could be met.

Sources

Reasoning

No case-control or case-cohort study of NM_017763.6:c.662G>A (p.Arg221Gln) was identified in the retrieved evidence; the variant has no published variant-specific case reports, and the ClinVar record for this exact variant (VCV001169480) carries no affected-versus-controls data (submission conditions are 'not provided'/'not specified'). Somatic occurrence counts (COSMIC, 3 records) do not constitute germline case-control enrichment evidence, and the general-population frequency of this variant (gnomAD v2.1 AF 0.49% overall, 6.0% East Asian; gnomAD v4.1 AF 0.25% overall, 7.2% East Asian, with homozygotes) is that of a common polymorphism rather than a rare disease allele, so PS4 cannot be credited under the generic ACMG/AMP 2015 framework.

Rule

ACMG/AMP 2015 PS4 (Richards et al., PMID:25741868): prevalence of the variant in affected individuals significantly increased versus controls; generic framework, no RNF43 VCEP specification.

Evidence considered

• Generic ACMG/AMP 2015 (PMID:25741868) PS4 definition reviewed: prevalence of the variant in affected individuals must be significantly increased compared with controls; no qualifying study exists for this variant.
• ClinVar VCV001169480 submissions for this exact variant report Benign from 8 clinical laboratories with conditions 'not provided'/'not specified'; no affected cohort or case-control comparison is described in any submission.
• The two literature candidates triaged as potential case-observation sources (PDQ reviews PMID:26389258 and PMID:26389505) had no retrievable abstract or full text in this case, so no variant-specific case reports could be confirmed from them.
• COSMIC records the variant as COSV68457520 with only 3 somatic cancer occurrences; somatic occurrence counts without controls do not demonstrate germline case-control enrichment.
• gnomAD v2.1 (AF 0.00488 overall; 0.0603 East Asian, 30 homozygotes) and gnomAD v4.1 (AF 0.00246 overall; 0.07195 East Asian, 136 homozygotes) show common-polymorphism population frequencies that are contextually inconsistent with a clinically significant case enrichment effect.

Still missing

• No published case-control or cohort enrichment study for RNF43 c.662G>A was retrievable; PS4 remains unevaluable in this evidence set until such a study exists.

Sources

Reasoning

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

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PM2 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PM3 (Richards et al. 2015) requires, for a recessive disorder, observation of the variant in trans with a pathogenic variant in an affected proband, ideally with phase established by parental testing. No RNF43 VCEP/CSPEC exists (vcep_materials: no cspec url; generic fallback), so the generic ACMG/AMP rule applies. The case evidence contains no proband, family, segregation, phase, or parental-testing observation of c.662G>A (p.Arg221Gln) in any source: ClinVar submissions (8 laboratories, all Benign, germline, conditions 'not provided'/'not specified') carry no allelic-phase or second-variant data, and the variant is absent from all case literature. Context: RNF43 germline disease is primarily monoallelic/autosomal dominant (serrated polyposis syndrome / CRC predisposition), and the only recessive/biallelic phenotype documented in the case literature involves a different, homozygous truncating allele (p.Gln636Ter, NM_001305545.1:c.1906C>T) in one consanguineous neurodevelopmental family. Even under that recessive scenario, c.662G>A is a common missense population polymorphism (gnomAD v2.1 AF 0.49% overall, 6.0% East Asian, 31 homozygotes) with no trans observation on record. Evidence is insufficient to apply PM3; the criterion is therefore not_assessed pending any allelic-phase or compound-heterozygote observation data.

Rule

Generic ACMG/AMP (Richards et al. 2015, PMID:25741868): PM3 - for recessive disorders, detected in trans with a pathogenic variant.

Evidence considered

• PM3 rule per Richards et al. 2015 (PMID:25741868): 'For recessive disorders, detected in trans with a pathogenic variant' - it requires the variant to be observed opposite a pathogenic allele in an affected proband, with phase ideally confirmed by parental testing; generic ACMG/AMP applies because no RNF43 VCEP/CSPEC was retrieved (generic_acmg_combination_rules).
• The case evidence contains no proband, segregation, phase, or parental-testing data for c.662G>A (p.Arg221Gln); the ClinVar record (variation 1169480) lists 8 germline submissions, all Benign, with conditions 'not provided'/'not specified' and no allelic-phase, zygosity, or co-occurring-variant content, so there is no trans observation to apply PM3 (clinvar).
• RNF43 germline disease context from the case's gene-context artifact (pvs1_gene_context): germline RNF43 disease is described as monoallelic - heterozygous/likely-pathogenic germline variants in serrated polyposis syndrome families (autosomal dominant cancer predisposition, e.g., Brinch et al. 2024, Fam Cancer); the only recessive presentation cited in the supporting literature is a homozygous truncating null variant p.Gln636Ter (NM_001305545.1:c.1906C>T, PMID 42196486 abstract) in a single consanguineous family with a neurodevelopmental phenotype - a different variant, mentioned only as inheritance-mode context.
• gnomAD v2.1 documents c.662G>A as a common polymorphism (overall AF 0.4878%, 1351/276972 alleles; East Asian AF 6.03%, 30 homozygotes; total 31 homozygotes), which provides population-frequency context only - cited here solely to show there is no recessive-disease-allele signal underpinning any trans-configuration hypothesis, not to adjudicate population-frequency criteria (gnomad_v2).

Still missing

• No observation of c.662G>A (p.Arg221Gln) in trans with a pathogenic RNF43 variant in any affected proband; no parental testing or phase-determination data exists in any consulted source.
• No RNF43 VCEP/CSPEC specification exists; under the generic ACMG/AMP rule PM3 presupposes a recessive disorder context, and the canonical RNF43 germline phenotype (serrated polyposis) is autosomal dominant. The recessive biallelic neurodevelopmental presentation documented in the literature used a different homozygous truncating allele and provides no observation of this variant.
• If proband/family sequencing data (phase, parental genotypes, second RNF43 allele) becomes available, PM3 must be re-evaluated.

Sources

Reasoning

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

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PM6 (assumed de novo without confirmation of parental relationship) cannot be evaluated for the same reason as PS2: the evidence bundle contains no proband record, no parental genotype data, and no de novo assertion for c.662G>A from any source. None of the 9 ClinVar submissions (VCV001169480) records a de novo occurrence or an assumed-de-novo case, and no fetched publication (only PMID:25741868 has full text/extraction) mentions this variant. PM6 therefore returns not_assessed due to insufficient evidence, with the primary gap being the total absence of proband/family genotype data rather than any conflicting observation.

Rule

ACMG/AMP 2015 (PMID:25741868) PM6: assumed de novo variant (parental relationship not confirmed) in a proband with the phenotype; moderate-strength de novo evidence per the 2015 framework

Evidence considered

• No de novo, parental, or trio data identified in any case-bundle artifact (review_manifest, case_summary, prefetch, evidence, literature_pass, paper_extracts)
• ClinVar submission audit: all SCVs for VCV001169480 list germline origin with 'not provided'/'not specified'/empty conditions and no assertion of de novo status
• paper_extracts.json PMID:25741868 consulted to confirm the generic PM6 definition (assumed de novo, unconfirmed parentage); the paper itself contains no variant-specific data
• Framework: generic ACMG/AMP 2015 (no RNF43 VCEP/CSPEC available), which assigns PM6 at moderate strength for assumed de novo with phenotype consistency when parental relationship is unconfirmed

Still missing

• No proband-parent trio genotype data from which an assumed de novo event (unconfirmed parentage) could be inferred
• No clinical report describing an individual carrying c.662G>A with the relevant phenotype and unaffected parents
• No variant-specific literature reporting de novo occurrence of c.662G>A (assumed or confirmed)

Sources

Reasoning

PP1 (co-segregation with disease in multiple affected family members) cannot be evaluated because no family or segregation data exists for this variant: there are no affected relatives tested, no pedigree, and no informative meiosis counts in the case bundle. The pvs1_gene_context literature search papers discuss other RNF43 variants (e.g., PMID:42196486 reports a homozygous truncating c.1906C>T variant segregating with a neurodevelopmental phenotype; PMID:39546056 reports different likely pathogenic variants in other families) - none is c.662G>A/p.(Arg221Gln), and segregation observed for a different variant cannot support PP1 for this variant. The only full-text-extracted paper (PMID:25741868) is the generic ACMG guidelines with no variant-specific segregation content. PP1 is therefore not_assessed pending actual co-segregation data for this exact variant.

Rule

ACMG/AMP 2015 (PMID:25741868) PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; supporting-to-strong strength scaled by informative meioses

Evidence considered

• No affected-family-member genotype or meiosis/segregation data present anywhere in the case bundle
• RNF43 germline literature surfaced for PVS1 gene context (PMID:33098683, PMID:42196486, PMID:28573495, PMID:39546056, PMID:41551532) concerns other RNF43 variants (frameshifts/nonsense/truncating and different missense variants), never c.662G>A; segregation of a different variant is not usable for PP1
• paper_extracts.json PMID:25741868 confirms the generic PP1 definition (co-segregation in multiple affected family members, strength graded by number of informative meioses) with no variant-specific data
• Framework: generic ACMG/AMP 2015 fallback (no RNF43 ClinGen specification exists)

Still missing

• No segregation analysis of c.662G>A in any family (no affected relatives genotyped, no informative meioses reported)
• No phenotype-consistent family with multiple affected carriers available to count co-segregating meioses
• No variant-specific case/cohort publication reporting segregation for c.662G>A; RNF43 germline segregation literature concerns other variants only

Sources

Reasoning

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

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PP3 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

PP4 requires the variant to be found in a proband whose phenotype or family history is highly specific for a disease caused by a gene with limited genetic heterogeneity. The case packet contains no proband phenotype, indication, or family-history information, and the ClinVar submissions for this exact variant carry no clinical phenotype detail (conditions listed as 'not provided'/'not specified', with only the gene-level condition label 'Sessile serrated polyposis cancer syndrome' on the record). Without the index case's phenotype, phenotype specificity cannot be evaluated.

Rule

ACMG/AMP 2015 PP4 (Richards et al., PMID:25741868): phenotype or family history highly specific for a gene with limited genetic heterogeneity; generic framework, no RNF43 VCEP specification.

Evidence considered

• Generic ACMG/AMP 2015 (PMID:25741868) PP4 definition reviewed: variant found in a proband with a phenotype or family history highly specific for the gene's disease.
• ClinVar VCV001169480 lists the RNF43-associated condition 'Sessile serrated polyposis cancer syndrome' on the record, but individual submissions carry 'not provided'/'not specified' or blank conditions; no proband phenotype detail is present.
• No phenotype, pedigree, or clinical summary content exists anywhere in the case evidence bundle for the tested individual.

Still missing

• No proband phenotype or clinical indication was provided in the case packet; PP4 requires this information and cannot be adjudicated from the available evidence.
• No gene-specific framework defines a PP4 phenotype-specificity rule for RNF43; serrated polyposis phenotype attribution would need human clinical review.

Sources

Reasoning

BA1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

BS1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

BS2 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

Under the governing generic ACMG/AMP 2015 framework (no RNF43 CSPEC/VCEP exists; vcep_materials.json framework_complete=false), BS3 requires well-established functional studies showing no damaging effect on protein function or splicing for the variant under evaluation. The case evidence set contains no functional assay of any kind for NM_017763.6:c.662G>A (p.Arg221Gln): OncoKB reports no variant-specific reviewed functional evidence ('Unknown Oncogenic Effect', no citations); the only full-text paper retrieved (PMID:25741868) is the ACMG framework document without any variant data; and no functional-study paper was triaged for this variant. The ClinVar 'Benign' classification (8 clinical laboratories) is an aggregate laboratory interpretation, not a functional study, and was not used to infer BS3. The no-damaging-effect premise of BS3 therefore cannot be established from any retrieved source.

Rule

BS3 (generic ACMG/AMP 2015, PMID:25741868): well-established functional studies show no damaging effect on protein function or splicing

Evidence considered

• Governing framework: generic ACMG/AMP 2015 fallback (Richards et al. 2015, PMID:25741868) defines BS3 as 'well-established functional studies show no damaging effect on protein function or splicing'; no RNF43-specific CSPEC/VCEP is available to calibrate BS3 further.
• OncoKB variant page for RNF43 R221Q (source registry key 'oncokb') returned 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence (is_variant_specific=false, not_reviewed=true); this documents absence of curated functional evidence, not a benign functional result, and cannot support BS3.
• paper_extracts.json (source registry key 'PMID:25741868'): ACMG framework paper only; no RNF43/c.662G>A/p.(R221Q) content and no functional data (variant_mentioned=false); nothing in it supports a no-damaging-effect conclusion for this variant.
• ClinVar (source registry key 'clinvar'; variation ID 1169480, Benign by 8 clinical laboratories) is an aggregate laboratory classification; a final classification from another source was not used to infer BS3.
• COSMIC COSV68457520 (source registry key 'cosmic') somatic occurrence (n=3) is not functional evidence for either direction and was not used for BS3.
• No functional-study paper was identified by literature_pass.json for this variant; the registry PMIDs (25741868, 26389258, 26389505, 28492532) are framework/review documents without variant-specific assay data.

Still missing

• No validated functional assay result for RNF43 p.(Arg221Gln)/c.662G>A showing preserved (wild-type-like) protein function was retrieved; such a controlled no-effect assay (e.g., Wnt/beta-catenin reporter or Frizzled ubiquitination/degradation readout) would be required before BS3 could be met.

Sources

Reasoning

BS4 (lack of segregation in affected family members) cannot be evaluated because no affected family members have been tested and no family/pedigree information exists for this variant in the case bundle. BS4 requires observed non-segregation (an affected relative who does not carry the variant, or equivalent), and the complete absence of family testing means the variant can neither be shown to segregate nor to fail to segregate. High population frequency (gnomAD v4.1 AF ~0.25% overall, ~7.2% in East Asians, 143 homozygotes) and ClinVar Benign assertions (8 laboratories) are relevant to population-frequency criteria handled by other groups (BA1/BS1/BS2) and were not used to score BS4, which specifically requires familial genotype evidence. BS4 is therefore not_assessed due to insufficient evidence.

Rule

ACMG/AMP 2015 (PMID:25741868) BS4: lack of segregation in affected family members (variant absent in an affected relative where it should co-segregate if causal)

Evidence considered

• No family-genotype or non-segregation observations exist for c.662G>A in any case-bundle artifact
• ClinVar submissions (VCV001169480) assert Benign without any segregation detail (evidence_signals empty across all 9 SCVs)
• paper_extracts.json PMID:25741868 consulted for the generic BS4 definition (lack of segregation in affected family members); contains no variant-specific data
• Population frequency and ClinVar assertions noted as context only and deliberately not used for BS4, which requires familial non-segregation rather than population data
• Framework: generic ACMG/AMP 2015 fallback (no RNF43 VCEP/CSPEC found)

Still missing

• No affected family members genotyped, so non-segregation (BS4) cannot be demonstrated
• No pedigree or family-history data attached to this case
• No variant-specific literature reporting absence of the variant in affected relatives

Sources

Reasoning

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

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

BP2 (Richards et al. 2015) is a benign supporting criterion applied when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern. No RNF43 VCEP/CSPEC exists, so the generic rule applies. The case evidence contains no allelic-phase observation of c.662G>A (p.Arg221Gln) in cis or in trans with any pathogenic RNF43 variant: ClinVar submissions (all Benign, germline) include no phase/co-occurrence data, and no proband or family observation appears in any consulted source. In addition, the RNF43 serrated polyposis phenotype is autosomal dominant with reduced/incompletely characterized penetrance, so even a trans observation would not satisfy the 'fully penetrant dominant' arm of BP2. Evidence is insufficient to apply BP2; the criterion is therefore not_assessed pending cis/trans co-occurrence observations.

Rule

Generic ACMG/AMP (Richards et al. 2015, PMID:25741868): BP2 - observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• BP2 rule per Richards et al. 2015 (PMID:25741868): observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern - a benign supporting criterion requiring direct allelic-phase observation; generic ACMG/AMP applies because no RNF43 VCEP/CSPEC was retrieved (generic_acmg_combination_rules).
• No cis or trans observation of c.662G>A with any pathogenic RNF43 variant appears anywhere in the case evidence; the ClinVar record (variation 1169480, 8 germline submissions, all Benign) contains no allele-phase, zygosity, or second-variant/co-occurrence content (clinvar).
• Gene-context literature in the case (pvs1_gene_context) describes RNF43 germline disease as monoallelic serrated-polyposis/CRC predisposition (autosomal dominant, incompletely characterized penetrance - e.g., Brinch et al. 2024 describe penetrance and phenotypic spectrum as poorly described), which is relevant to the 'fully penetrant dominant' precondition of the BP2 trans arm.

Still missing

• No observation of c.662G>A (p.Arg221Gln) in cis with a pathogenic RNF43 variant (any inheritance pattern) or in trans with a pathogenic variant in a fully penetrant dominant disorder exists in the case evidence.
• ClinVar submissions for this variant contain no allelic-phase or co-occurring-variant data, and no family/segregation observations were retrieved for this case.
• RNF43 germline predisposition (serrated polyposis) is autosomal dominant with incompletely characterized penetrance; demonstration of full penetrance would be needed for the trans arm of BP2 to ever apply.

Sources

Reasoning

BP4 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: Hermes timed out after 200s and left no usable output_file
• attempt 2: Hermes timed out after 200s and left no usable output_file
• attempt 3: Hermes timed out after 200s and left no usable output_file

Reasoning

BP5 requires identification of an alternative molecular basis of disease in the tested individual (e.g., a pathogenic variant in another gene that fully explains the phenotype). The case packet contains no proband-level data beyond the single RNF43 variant - no secondary variant findings, no phenotype, and no pedigree - so the presence or absence of an alternative molecular explanation cannot be assessed.

Rule

ACMG/AMP 2015 BP5 (Richards et al., PMID:25741868): variant found in a case with an alternate molecular basis for disease; requires case-level genotype/phenotype data not present here.

Evidence considered

• ClinVar VCV001169480 submissions describe only this single RNF43 variant; none of the submissions reports an alternative molecular diagnosis in the tested individual.
• No case-level content (other-gene variant findings, phenotype, or family history) exists anywhere in the case evidence bundle, so an alternative molecular basis can be neither confirmed nor excluded.

Still missing

• No proband-level genotype or phenotype data (e.g., a concurrently identified pathogenic variant in another gene) were provided; BP5 requires case-level information that is absent from this evidence set.

Sources