FGFR2 c.819C>G, p.(Asp273Glu)

Reasoning

PM2 is met at supporting strength under the generic ACMG/AMP fallback. The variant is extremely rare across both gnomAD releases, has a low gnomAD v4.1 grpmax FAF, and has no observed homozygotes; it is also absent from gnomAD-Canada v1.0. These data do not contradict rarity for an FGFR2-related disorder.

Rule

Generic ACMG/AMP PM2: absent from controls or present at extremely low frequency when population data support rarity for the disorder; applied at supporting strength in the generic fallback.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP population-frequency criteria were used.
• gnomAD v4.1 reports 2/1,614,080 alleles (AF 1.2391e-06), African/African American AF 2.66859e-05, grpmax FAF 4.43e-06, and zero homozygotes.
• gnomAD v2.1 reports 2/282,804 alleles (AF 7.07204e-06), maximum African/African American AF 8.00961e-05, and zero homozygotes.
• gnomAD-Canada v1.0 reports the variant absent.

Still missing

• No FGFR2 CSPEC/VCEP or local gene-specific PM2 frequency calibration was retrieved; the generic supporting application should be superseded if an applicable specification becomes available.

Sources

Reasoning

No governing VCEP/gene-specific framework was found for FGFR2, so generic ACMG/AMP in-silico assessment applies (framework_mode: generic_acmg). NM_000141.4:c.819C>G (p.(Asp273Glu)) is a missense variant with REVEL score = 0.129, a low score consistent with a benign/tolerated prediction. SpliceAI max delta score = 0.007 is also consistent with no predicted splicing impact, in agreement with the missense-tool prediction rather than conflicting with it. Both independent computational lines of evidence (missense predictor and splice predictor) concordantly predict no deleterious effect, supporting BP4 at supporting strength. BayesDel score (-0.146232) exists but is intentionally excluded from this determination because no verified published calibration threshold for BayesDel is available to this pipeline; this is a documented pipeline limitation, not evidence against BP4.

Rule

Generic ACMG/AMP BP4 (multiple lines of computational evidence suggest no impact on gene product): applied at supporting strength based on concordant low REVEL score and near-zero SpliceAI delta scores.

Evidence considered

• REVEL score 0.129 for NM_000141.4:c.819C>G (p.Asp273Glu), retrieved from local REVEL v1.3 predictor lookup; a low score supports a benign/tolerated in-silico prediction.
• SpliceAI Lookup max delta score = 0.007 (DS_AG 0.0, DS_AL 0.002, DS_DG 0.007, DS_DL 0.002) for NM_000141.4:c.819C>G, well below the ~0.2 high-recall cutoff from the original SpliceAI publication (Jaganathan et al., Cell 2019, PMID 30661751); no splice-altering effect predicted, concordant with the missense predictor.

Still missing

• BayesDel score exists (-0.146232) but is not usable for BP4 because no verified published calibration threshold/PMID for BayesDel is available to this pipeline; if a verified threshold becomes available, re-evaluate whether it changes strength.

Sources

Reasoning

No governing VCEP/gene-specific framework was found for FGFR2 (cspec.found=false, vcep_materials.final_classification_framework.found=false), so generic ACMG/AMP in-silico assessment applies. NM_000141.4:c.819C>G (p.(Asp273Glu)) is a missense variant. REVEL score = 0.129, well below the benign-supporting range and far from any pathogenic-supporting cutoff, so it does not support PP3. SpliceAI max delta score = 0.007 (DS_AG 0.0, DS_AL 0.002, DS_DG 0.007, DS_DL 0.002), far below the ~0.2 high-recall threshold established in the original SpliceAI benchmarking, so no splice-altering effect is predicted and this does not support PP3 via the splice-impact path either. BayesDel score (-0.146232) is available but is not used here because no verified published calibration threshold for BayesDel is available to this pipeline. No lines of calibrated computational evidence support a pathogenic/damaging effect.

Rule

Generic ACMG/AMP PP3 (computational evidence supports a deleterious effect) not triggered: REVEL score is low and SpliceAI delta scores are near zero.

Evidence considered

• REVEL score 0.129 for NM_000141.4:c.819C>G (p.Asp273Glu), retrieved from local REVEL v1.3 predictor lookup; low score is inconsistent with a damaging missense prediction.
• SpliceAI Lookup (spliceailookup.broadinstitute.org) max delta score = 0.007 for NM_000141.4:c.819C>G, well below the ~0.2 high-recall cutoff established in the original SpliceAI publication (Jaganathan et al., Cell 2019, PMID 30661751), indicating no predicted splicing impact.

Still missing

• BayesDel score exists (-0.146232) but cannot be used for PP3/BP4 because no verified published calibration threshold/PMID is available to this pipeline.

Sources

Reasoning

PP5 is not met because no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion is available. The ClinVar audit records zero expert-panel submissions and identifies the audited submissions as non-expert, non-exact records; they cannot trigger PP5.

Rule

Applied only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion; no FGFR2 VCEP/CSPEC was retrieved.

Evidence considered

• The ClinVar submission audit reports expert_panel_submissions=0 and shows all three audited Likely benign laboratory submissions as is_expert_panel=false and exact_variant_match=false.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification would be required.

Sources

Reasoning

BA1 is not met. The observed allele frequency is far below the generic ACMG/AMP stand-alone benign frequency threshold and is incompatible with a high-frequency benign assignment.

Rule

Generic ACMG/AMP BA1: an allele frequency greater than 5% is stand-alone benign evidence.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP population-frequency criteria were used.
• gnomAD v4.1 reports 2/1,614,080 alleles (AF 1.2391e-06), with an African/African American maximum observed AF of 2.66859e-05 and grpmax FAF 4.43e-06; there are no homozygotes.
• gnomAD v2.1 reports 2/282,804 alleles (AF 7.07204e-06), maximum African/African American AF 8.00961e-05, and no homozygotes.

Sources

Reasoning

BS1 is not met. The highest observed population frequency and the gnomAD v4.1 grpmax FAF are extremely low and do not establish a frequency greater than expected for an FGFR2-related disorder.

Rule

Generic ACMG/AMP BS1: allele frequency is greater than expected for the disorder.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP population-frequency criteria were used.
• gnomAD v4.1: 2/1,614,080 alleles overall (AF 1.2391e-06), African/African American AF 2.66859e-05, and grpmax FAF 4.43e-06; no homozygotes.
• gnomAD v2.1: 2/282,804 alleles overall (AF 7.07204e-06), with maximum African/African American AF 8.00961e-05; no homozygotes.

Still missing

• No FGFR2 disease- and penetrance-specific BS1 maximum credible allele-frequency threshold was retrieved; therefore no gene-specific benign frequency threshold was applied.

Sources

Reasoning

BP6 is not met because no exact-variant ClinVar expert-panel Benign/Likely benign assertion is available. The ClinVar audit records zero expert-panel submissions and identifies the audited Likely benign laboratory submissions as non-expert, non-exact records; they cannot trigger BP6.

Rule

Applied only for an exact-variant ClinVar expert-panel Benign/Likely benign assertion; no FGFR2 VCEP/CSPEC was retrieved.

Evidence considered

• The ClinVar submission audit reports expert_panel_submissions=0 and shows all three audited Likely benign laboratory submissions as is_expert_panel=false and exact_variant_match=false.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign classification would be required.

Sources

Reasoning

PS1 requires an established pathogenic/likely pathogenic variant that produces the identical amino acid change (p.Asp273Glu) via a different nucleotide substitution. No FGFR2 gene-specific VCEP/CSPEC exists (case_summary.cspec.found=false; framework_mode=generic_acmg), so generic ACMG PS1 logic applies. The ClinVar search for this exact variant returned no_exact_match (the retrieved ClinVar record 1328666 is titled NM_000141.5(FGFR2):c.1155C>G p.(Val385=), a different variant), so no same-amino-acid-change comparator classification was retrieved from ClinVar in this bundle, and no other database in the evidence bundle (OncoKB, cancerhotspots.org, literature) reports an alternate codon producing p.Asp273Glu with an established pathogenic classification.

Evidence considered

• case_summary.compact_evidence.clinvar reports search_status/evidence_sentence 'Error retrieving ClinVar entry.' and the returned ClinVar record title (NM_000141.5(FGFR2):c.1155C>G, p.(Val385=)) does not match the queried c.819C>G/p.(Asp273Glu) variant, flagged by the pipeline as no_exact_match.
• No alternate-codon p.Asp273Glu comparator variant was located in any prefetched source (ClinVar, OncoKB, literature_pass) within this evidence bundle.

Still missing

• No confirmed same-amino-acid-change (p.Asp273Glu via alternate codon) comparator variant with an established pathogenic/likely pathogenic ClinVar or literature classification was found in the collected evidence.
• ClinVar search for the exact queried variant returned no_exact_match, so PS1 cannot be evaluated against a verified same-residue same-change record from this bundle.

Sources

Reasoning

No case-level evidence establishes that NM_000141.4:c.819C>G occurred de novo in an affected proband with maternity and paternity confirmed.

Rule

Generic ACMG/AMP 2015 PS2: confirmed de novo occurrence requires the variant in a patient with the disease and confirmed maternity and paternity.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was provided; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle contains no proband-level observation, parental testing result, parentage confirmation, or de novo report for NM_000141.4:c.819C>G.

Still missing

• Proband phenotype and molecular result
• Maternal and paternal genotype results for the exact variant
• Confirmation of biological parentage and test methodology

Reasoning

No functional/biochemical assay data (e.g., FGFR2 kinase activity, receptor dimerization/autophosphorylation, osteoblast differentiation, cell proliferation assays) for NM_000141.4:c.819C>G (p.Asp273Glu) were found anywhere in the case bundle. No ClinGen VCEP CSPEC was located for FGFR2 in this case (cspec.found=false), so no gene-specific functional-assay calibration is available; generic ACMG/AMP framework applies but no validated assay evidence exists to apply it to. Literature triage identified only GeneReviews overview chapters (PMIDs 20301368, 20301592, 20301628, 31145570) and background methodology papers (ACMG/AMP guideline PMID 25741868; Sherloc PMID 28492532) — none of which report a functional assay of this variant.

Still missing

• No published functional/biochemical assay (kinase activity, dimerization, downstream signaling, or cell-based proliferation/differentiation assay) for c.819C>G (p.Asp273Glu) identified in the literature triage or full-text set.
• No FGFR2 ClinGen VCEP-specific functional assay calibration (validated assay list, thresholds) available in this case's vcep_materials.

Reasoning

No case-control or cohort enrichment data for NM_000141.4:c.819C>G (p.Asp273Glu) were provided. The PS4 screen contains no screened or passing studies.

Rule

Generic ACMG/AMP fallback: PS4 requires statistically increased prevalence in affected individuals compared with controls; no FGFR2 VCEP/CSPEC was retrieved.

Evidence considered

• The supplied PS4 screening record reports screened=0 and no passing studies; no case-control enrichment evidence is available in the case bundle.

Still missing

• A variant-specific, adequately ascertained case-control or cohort study reporting affected and control counts is needed.

Reasoning

PM1 requires the variant to fall in a well-established functional/mutational hotspot or critical, well-characterized functional domain without benign variation. No FGFR2 VCEP/CSPEC domain map is available (cspec.found=false). The only structured hotspot lookup performed, cancerhotspots.org (a somatic/oncology recurrence database, queried as 'FGFR2 D273'), returned no_result / 'This variant does not lie in a statistically significant hotspot,' which is negative evidence but reflects a somatic-cancer recurrence resource rather than a germline missense mutational cluster or curated domain boundary annotation. The evidence bundle contains no UniProt/Pfam-style domain coordinate data placing residue 273 in a specific named FGFR2 domain (e.g., Ig-like domain III vs. linker) that would let this residue be evaluated against domain-level constraint.

Evidence considered

• evidence.json hotspots (CANCERHOTSPOTS, query 'FGFR2 D273'): search_status no_result, evidence_sentence 'This variant does not lie in a statistically significant hotspot.' This source key is not present in source_registry.json, so it is not cited in evidence_refs, but is noted here as the only hotspot-adjacent lookup performed.
• No domain-boundary database (UniProt/Pfam) output for FGFR2 residue 273 was present anywhere in the consolidated evidence bundle.

Still missing

• No gene-specific VCEP/CSPEC PM1 domain or hotspot table is available for FGFR2 in this case.
• The only hotspot query performed (cancerhotspots.org, a somatic cancer recurrence database) found no significant hotspot at D273, but this source is not a germline-disease domain/hotspot resource and does not establish domain boundaries.
• No structured protein domain annotation (e.g., UniProt Ig-like domain III coordinates) for residue 273 was captured in this evidence bundle to confirm or refute placement in a critical functional domain.

Reasoning

No affected-proband observation of NM_000141.4:c.819C>G with a second FGFR2 variant, no pathogenic/likely pathogenic comparator variant, and no phase result are present in the consolidated evidence. Under the generic ACMG/AMP framework, PM3 requires a variant in trans with a pathogenic variant in a recessive disorder; this cannot be assessed from the available case evidence.

Rule

Generic ACMG/AMP 2015 PM3: moderate evidence requires a pathogenic variant in trans in a recessive disorder; multiple trans observations may support stronger evidence.

Evidence considered

• No FGFR2 co-occurring variant, affected-proband observation, or cis/trans phase result was supplied in the consolidated case-evidence bundle.
• Generic ACMG/AMP guidance (PMID:25741868, section 3, 'PM3 BP2 Cis/trans testing') states: 'when two heterozygous variants are identified in a gene for a recessive disorder, if one variant is known to be pathogenic, then determining that the other variant is in trans can be considered moderate evidence for pathogenicity of the latter variant (PM3).'

Still missing

• Affected-proband genotype data identifying any second FGFR2 variant.
• Validated pathogenicity assessment of any second variant and parental or other phase data demonstrating trans configuration.
• Case-specific disease diagnosis and inheritance model confirming relevance of a recessive FGFR2 mechanism.

Sources

Reasoning

PM5 requires a different missense change at the same residue (D273) previously established as pathogenic/likely pathogenic. The pipeline's own pm5_candidates_summary explicitly reports pm5_mode='unknown', eligible_for_classic_pm5_search=false, and a recommendation level of 'not_applicable' with the instruction 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting' and 'do not apply PM5 from this artifact alone.' The candidate_summary shows zero candidates of any kind were collected (total_candidates_seen=0, same_residue_candidates=0). No other source in the bundle (ClinVar, OncoKB, literature) independently identifies an alternate pathogenic missense change at codon 273.

Evidence considered

• pm5_candidates_summary in the case bundle: pm5_mode='unknown', eligible_for_classic_pm5_search=false, recommendation.level='not_applicable', recommendation.summary='Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting,' candidate_summary.total_candidates_seen=0 and same_residue_candidates=0.

Still missing

• pm5_candidates.json harvesting was explicitly skipped by the pipeline pending confirmation of PM5 semantics; zero same-residue comparator variants were collected.
• No manual search for alternate pathogenic missense substitutions at FGFR2 residue 273 (e.g., other D273X changes) has been performed or captured in this evidence bundle.

Sources

Reasoning

No case-level evidence reports NM_000141.4:c.819C>G as a presumed de novo variant in an affected proband without confirmation of both parental relationships.

Rule

Generic ACMG/AMP 2015 PM6: presumed de novo occurrence requires the variant in a patient with the disease when maternity and paternity are not confirmed.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was provided; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle contains no proband-level observation, parental testing result, parentage information, or presumed de novo report for NM_000141.4:c.819C>G.

Still missing

• Proband phenotype and molecular result
• Parental genotypes for the exact variant
• Whether maternity and paternity were confirmed

Reasoning

No informative family genotypes, affected-status data, or count of independent segregations/meioses is available for NM_000141.4:c.819C>G.

Rule

Generic ACMG/AMP 2015 PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease may support pathogenicity.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was provided; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle contains no family segregation data for NM_000141.4:c.819C>G.

Still missing

• Pedigree with phenotype status of tested relatives
• Genotypes for the exact variant in affected and unaffected relatives
• Number of informative meioses and assessment of phenocopies, age-dependent penetrance, and variable expressivity

Reasoning

PP2 requires (1) the gene to have a low rate of benign missense variation and (2) missense to be a common/established mechanism of disease in that gene. FGFR2 is broadly known to cause craniosynostosis and related skeletal syndromes predominantly through activating missense variants, and case_summary.compact_evidence.clinvar lists GeneReviews chapter titles consistent with a missense-driven disease spectrum (e.g., 'FGFR Craniosynostosis Syndromes Overview,' 'Saethre-Chotzen Syndrome,' 'Apert Syndrome'), but only titles (no abstract text or direct quotes) for these entries were retrieved in this bundle, so the specific 'common mechanism of disease' claim cannot be directly quoted/grounded from the collected sources. No missense constraint metric (e.g., gnomAD missense Z-score or observed/expected missense ratio) for FGFR2 was captured anywhere in the evidence bundle, so the 'low rate of benign missense variation' prong cannot be verified from the data available in this case.

Evidence considered

• case_summary.compact_evidence.clinvar.pmids_with_titles lists FGFR2-relevant GeneReviews chapters (PMID 20301628 'FGFR Craniosynostosis Syndromes Overview', PMID 20301368 'Saethre-Chotzen Syndrome', PMID 31145570 'Apert Syndrome'), consistent with FGFR2 disease being predominantly missense/gain-of-function driven, but only titles were retrieved (no abstract or full-text snippet), so this cannot be used as a directly quoted, grounded citation for the PP2 mechanism prong.
• No missense-specific gene constraint statistic (gnomAD missense Z-score/o-e) for FGFR2 appears anywhere in prefetch.json, evidence.json, or case_summary.json in this bundle.

Still missing

• No gnomAD missense constraint metric (missense Z-score / o-e ratio) for FGFR2 is present in the evidence bundle to support the 'low rate of benign missense variation' prong of PP2.
• The GeneReviews chapters referenced in ClinVar citations (PMID:20301628, PMID:20301368, PMID:31145570) were retrieved only as titles, without abstract/full-text content, so a directly quoted statement establishing missense as the predominant FGFR2 disease mechanism could not be extracted from this bundle.

Reasoning

The bundle provides no proband phenotype, clinical diagnosis, or phenotype-to-gene differential assessment for the individual carrying this variant. Phenotypic specificity cannot be evaluated.

Rule

Generic ACMG/AMP fallback: PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology; no FGFR2 VCEP/CSPEC was retrieved.

Evidence considered

• No individual-level phenotype or diagnostic workup for the tested person is present in the consolidated case-evidence bundle.

Still missing

• Detailed proband phenotype and diagnostic workup are needed to determine whether the presentation is highly specific for an FGFR2-related disorder and whether alternative causes have been assessed.

Reasoning

BS2 is not assessed. Population counts show no homozygotes, and no phenotype-annotated healthy adult observations or disease-specific penetrance evidence were provided. Rare heterozygous alleles in aggregate populations do not by themselves meet BS2.

Rule

Generic ACMG/AMP BS2 requires observation in healthy adult individuals for a disorder with full penetrance expected at an early age.

Evidence considered

• gnomAD v4.1 reports no homozygotes among 1,614,080 alleles; its two observations are in the African/African American population.
• gnomAD v2.1 also reports no homozygotes among 282,804 alleles.

Still missing

• Phenotype-annotated observations of this exact variant in healthy adults, together with disease-specific age of onset and penetrance information sufficient to judge BS2 applicability.

Sources

Reasoning

No functional/biochemical assay data for NM_000141.4:c.819C>G (p.Asp273Glu) were found anywhere in the case bundle, and no FGFR2 CSPEC was located to define validated benign-range assay controls or thresholds. Literature triage returned only GeneReviews overview chapters and generic ACMG/Sherloc methodology papers, none reporting a functional study of this specific variant, so a normal/wild-type-range assay result cannot be confirmed.

Still missing

• No published functional assay showing wild-type/normal-range activity for c.819C>G (p.Asp273Glu) identified in the literature triage or full-text set.
• No FGFR2 ClinGen VCEP-specific functional assay calibration (validated assay list, thresholds, negative controls) available in this case's vcep_materials.

Reasoning

No informative non-segregation evidence shows the exact variant in unaffected relatives or its absence from affected relatives in a manner supporting lack of cosegregation.

Rule

Generic ACMG/AMP 2015 BS4: lack of segregation in affected members of a family supports a benign interpretation when the family data are informative.

Evidence considered

• No FGFR2 CSPEC/VCEP or local gene-specific framework was provided; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle contains no informative family non-segregation data for NM_000141.4:c.819C>G.

Still missing

• Pedigree with phenotype status, ages, and relevant clinical evaluation of relatives
• Genotypes for the exact variant in informative affected and unaffected relatives
• Assessment of penetrance, variable expressivity, phenocopies, and age at examination

Reasoning

BP1 requires the gene to be one in which disease is caused primarily by truncating/loss-of-function variants, making a missense variant less likely pathogenic on mechanism grounds alone. The pvs1_gene_context in this bundle states lof_mechanism_supported=true with mechanism_rationale 'Targeted germline literature review identified disease-focused publications supporting FGFR2 loss of function as a germline disease mechanism,' indicating an LOF mechanism does exist for at least some FGFR2 phenotypes, but this same evidence set (and the GeneReviews titles cited in case_summary) equally documents extensive missense-driven, activating disease mechanisms (craniosynostosis syndromes). The bundle does not contain a quantitative breakdown of the relative proportion of truncating versus missense pathogenic variants in FGFR2-related disease, so it cannot be determined from the collected sources whether truncating variants are the primary mechanism as BP1 requires.

Evidence considered

• pvs1_gene_context.lof_mechanism_supported=true, mechanism_rationale: 'Targeted germline literature review identified disease-focused publications supporting FGFR2 loss of function as a germline disease mechanism, so generic PVS1 framework assessment is eligible.' This documents that an LOF disease mechanism exists for FGFR2 but does not quantify it as the primary mechanism versus missense/activating mechanisms, so it is insufficient alone to establish or refute BP1.

Still missing

• No quantitative comparison of truncating vs. missense pathogenic variant proportions for FGFR2 is present in the evidence bundle.
• pvs1_gene_context establishes that an LOF mechanism is supported for FGFR2 in some contexts, but does not establish that truncating variants are the primary/predominant disease mechanism required for BP1, and the same bundle also documents missense/activating mechanisms for craniosynostosis phenotypes, creating an unresolved mixed-mechanism picture.

Sources

Reasoning

No individual with NM_000141.4:c.819C>G and a second established pathogenic FGFR2 variant is documented, and no cis/trans phase result is available. Therefore neither the recessive cis scenario nor the dominant trans scenario described by generic ACMG/AMP guidance can be evaluated.

Rule

Generic ACMG/AMP 2015 BP2: supporting benign evidence may derive from cis co-occurrence with a pathogenic variant in a recessive disorder or trans co-occurrence with a pathogenic variant in a dominant disorder, subject to disease-model relevance.

Evidence considered

• No FGFR2 co-occurring variant, affected-proband observation, or cis/trans phase result was supplied in the consolidated case-evidence bundle.
• Generic ACMG/AMP guidance (PMID:25741868, section 3, 'PM3 BP2 Cis/trans testing') states: 'finding the second variant in cis would be supporting evidence, though not definitive, for a benign role (BP2)' and, 'In the context of dominant disorders, the detection of a variant in trans with a pathogenic variant can be considered supporting evidence for a benign impact (BP2).'

Still missing

• Documented co-occurrence of NM_000141.4:c.819C>G with an established pathogenic/likely pathogenic FGFR2 variant in the same individual.
• Parental or molecular phase data establishing cis configuration for a relevant recessive model or trans configuration for a relevant dominant model.
• Case-specific disease diagnosis and inheritance model.

Sources

Reasoning

No proband-level evidence of an alternate molecular diagnosis that fully explains the phenotype is provided.

Rule

Generic ACMG/AMP fallback: BP5 requires a variant in a case with an alternate molecular basis for disease; no FGFR2 VCEP/CSPEC was retrieved.

Evidence considered

• No phenotype or alternate molecular diagnosis for the tested person is present in the consolidated case-evidence bundle.

Still missing

• A documented alternate molecular diagnosis and evidence that it fully explains the individual's phenotype are needed.