POLE c.4307G>A, p.(Arg1436Gln)

Reasoning

PS1 requires a previously established pathogenic variant producing the same amino-acid change. The governing POLE material identifies the established pathogenic substitutions as P286R, V411L, S297F, A456P, and S459F, and identifies other exact pathogenic non-hotspot variants, but does not establish p.R1436Q or any pathogenic variant producing the Arg1436Gln change. Supplementary Table S1 records p.R1436Q once in COSMIC and zero times in TCGA, which is recurrence information rather than evidence of a known pathogenic same-amino-acid substitution.

Rule

Generic PS1: a previously established pathogenic variant causes the same amino-acid change; no applicable POLE-specific PS1 rule was supplied.

Evidence considered

• PATH-250-323.pdf identifies P286R, V411L, S297F, A456P, and S459F as the five established pathogenic POLE exonuclease-domain substitutions; p.R1436Q is not among them.
• PATH-250-323-s002.xlsx lists p.R1436Q/c.4307G>A with COSMIC count 1, TCGA count 0, and total count 1; this does not establish same-amino-acid pathogenicity.
• The local POLE framework supplies exact pathogenic substitution lists for PM1 but no same-amino-acid PS1 rule or pathogenic p.R1436Q designation.

Still missing

• No published same-amino-acid pathogenic comparator for p.Arg1436Gln was identified in the reviewed evidence.
• PATH-250-323-s001.tif full text is unavailable and could not be searched for a same-amino-acid comparator.

Sources

Reasoning

PS4 is not met under the governing POLE somatic-recurrence framework. PATH-250-323-s002 contains an exact entry for p.R1436Q / c.4307G>A with 1 COSMIC case, 0 TCGA cases, and total 1. The PATH-250-323 paper defines a recurrent mutation as one present in two or more combined COSMIC and TCGA samples: 1 >= 2? no. The variant is also not one of the five established hotspot mutations or one of the 11 variants listed as pathogenic by the POLE-score. This somatic endometrial-carcinoma recurrence context is not a germline case-control enrichment result, and no patient-level phenotype cohort or odds ratio is available.

Rule

POLE local framework: somatic PS4 is a recurrence adaptation capped at Supporting; PATH-250-323 defines recurrent as >=2 combined COSMIC/TCGA samples. Exact comparison: 1 >= 2? no.

Evidence considered

• PATH-250-323-s002 exact row: p.R1436Q, c.4307G>A, COSMIC count 1, TCGA count 0, total count 1.
• PATH-250-323 states that recurrent mutations were defined as present in two or more cancer samples in COSMIC and TCGA combined, with duplicate cases counted once; the substituted comparison is 1 >= 2? no.
• PATH-250-323 identifies P286R, V411L, S297F, A456P, and S459F as the five established hotspot mutations and lists 11 pathogenic POLE EDMs in Table 3; p.R1436Q is not among them.
• The available evidence is somatic endometrial-carcinoma recurrence context rather than a germline phenotype-specific case-control enrichment study.

Still missing

• PATH-250-323-s001.tif was unavailable for text conversion and could not be reviewed visually in this assessment.
• No germline case-control enrichment statistic, odds ratio, or phenotype-defined affected-case cohort is available.

Sources

Reasoning

The local POLE framework is the applicable gene-specific specification and defines PM1 only for exact listed variants: five established hotspots at strong strength, six exact recurrent pathogenic non-hotspot variants at moderate strength, and four exact recurrent uncertain-tier variants at supporting strength. p.R1436Q is absent from all three lists. The governing paper further distinguishes the exonuclease domain from mutations outside it and states that most mutations outside the exonuclease domain are not pathogenic; the reviewed table places R1436Q among non-hotspot variants and provides no approved PM1 assignment. vcep_materials.json has no domain_tables entry for POLE, so there is no authoritative domain-table interval requiring an additional positive match.

Rule

POLE-specific PM1: apply only to the exact variants in the three framework lists; no generic domain inference may replace the absent exact assignment.

Evidence considered

• The POLE framework assigns PM1 only to exact substitutions: P286R, V411L, S297F, A456P, S459F; F367S, L424I, M295R, P436R, M444K, D368Y; or A465V, L424V, T278M, A428T. R1436Q is absent.
• PATH-250-323.pdf states that only one of 23 tumors with a non-exonuclease-domain POLE mutation showed the characteristic alterations and that most mutations outside the exonuclease domain are not pathogenic.
• PATH-250-323-s002.xlsx records R1436Q as a single COSMIC case with no TCGA cases, not as one of the established hotspot or exact PM1 pathogenic sets.
• vcep_materials.json reports domain_tables as an empty object, so no authoritative POLE domain-table entry supports PM1 for residue 1436.

Still missing

• vcep_materials.json contains no POLE domain_tables entry; therefore no extracted authoritative domain interval was available beyond the governing paper's domain discussion.
• PATH-250-323-s001.tif full text is unavailable and could not be searched for an additional domain or hotspot assignment.

Sources

Reasoning

PM2 is not met under the supplied generic supporting threshold of allele frequency <=0.0001 when the all-comers dataset is the default. Although the overall gnomAD v4.1 frequency is 3.34575e-05, the variant reaches 0.000216652 in the Admixed American population and has a gnomAD v4.1 group maximum frequency of 0.00012744, both exceeding 0.0001. The POLE local framework does not specify a population source or PM2 threshold, so the default all-comers dataset and supplied generic threshold apply; non-cancer subsets are therefore not substituted.

Rule

Generic PM2: allele frequency <=0.0001; use all-comers gnomAD by default unless a governing VCEP specifies a different population source; no applicable POLE-specific PM2 rule.

Evidence considered

• gnomAD v4.1 reports overall AF 3.34575e-05, highest population AF 0.000216652 in Admixed American individuals, and group-maximum FAF 0.00012744.
• The POLE local framework has no PM2 population-source or threshold specification, so the supplied generic PM2 threshold of <=0.0001 and default all-comers gnomAD dataset were used.
• The available gnomAD v2.1 non-cancer exome and v3.1 non-cancer genome records are not substituted because no governing POLE specification requires a non-cancer or exome-only source.

Sources

Reasoning

This is a missense variant, so PP3 must use the REVEL path only. The governing POLE Supplementary Table S3 includes R1436Q and assigns REVEL class Likely-benign with one benign in-silico result, not the custom PP3 requirement of likely disease causing with no more than one benign result. The case REVEL score is 0.42, below the generic PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used because splice predictions cannot provide PP3 evidence for a missense consequence.

Rule

For a missense variant, use REVEL only. The POLE custom PP3 rule requires exact presence in Supplementary Table S2 or S3, a likely disease-causing REVEL class, and <=1 benign in-silico result; otherwise generic REVEL PP3 supporting requires >=0.644.

Evidence considered

• Case REVEL score is 0.42; the published generic PP3 supporting threshold is >=0.644, from ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
• POLE PATH-250-323-s004.xlsx Supplementary Table S3 lists R1436Q as Likely-benign with one benign result among the in-silico tools; the POLE custom PP3 rule requires a likely disease-causing REVEL class and <=1 benign result.
• SpliceAI max delta 0.608 was not used because this missense variant must be adjudicated through the REVEL path, not the splice-impact path.

Still missing

• The exact variant was not found in PATH-250-323-s003.xlsx.txt under c.4307G>A, Arg1436Gln, or R1436Q; the applicable S004 entry was available.

Sources

Reasoning

PP5 is not met. The exact ClinVar record for NM_006231.4:c.4307G>A (p.Arg1436Gln) has zero expert-panel submissions; its available classifications are ordinary single-submitter laboratory assertions consisting of six uncertain-significance submissions and one likely-benign submission. PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification, which is absent.

Rule

PP5 applies only when the exact variant has a ClinVar expert-panel classification of Pathogenic or Likely pathogenic; none is present.

Evidence considered

• ClinVar variation 473660 exactly matches NM_006231.4:c.4307G>A (p.Arg1436Gln) and reports expert_panels as an empty object with expert-panel submission count 0.
• The exact-variant ClinVar submissions are single-submitter laboratory assertions: six Uncertain significance and one Likely benign; no Pathogenic or Likely pathogenic expert-panel assertion is present.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from PP5 under the specified rule.

Sources

Reasoning

BA1 is not met. Under the generic ACMG/AMP stand-alone threshold of allele frequency >=0.05, the highest reported all-comers frequency is 0.000216652 in the Admixed American population in gnomAD v4.1, and the overall frequency is 3.34575e-05 (54/1613988 alleles); both are far below 0.05. The POLE local framework customizes PM1, PS4, PP3, and BP4, but provides no population-specific BA1 rule, so generic criteria apply.

Rule

Generic ACMG/AMP BA1: allele frequency >=0.05; no applicable POLE-specific BA1 rule.

Evidence considered

• gnomAD v4.1 reports an overall allele frequency of 3.34575e-05 from 54/1613988 alleles, with the highest population frequency 0.000216652 in Admixed American individuals.
• No applicable POLE-specific population-frequency rule is provided; the generic ACMG/AMP BA1 threshold of 0.05 was therefore used.

Sources

Reasoning

BS1 is not met. Under the generic strong benign threshold of allele frequency >=0.01, the highest reported all-comers frequency is 0.000216652 in the Admixed American population in gnomAD v4.1, and the overall frequency is 3.34575e-05; neither reaches 0.01. The POLE local framework does not specify BS1, so the supplied generic threshold applies.

Rule

Generic BS1: allele frequency >=0.01; no applicable POLE-specific BS1 rule.

Evidence considered

• gnomAD v4.1 reports an overall allele frequency of 3.34575e-05 and a highest population frequency of 0.000216652 in Admixed American individuals.
• No applicable POLE-specific BS1 frequency threshold is provided; the supplied generic BS1 threshold of 0.01 was used.

Sources

Reasoning

This is a missense variant, so BP4 must use the REVEL path only. The governing POLE Supplementary Table S3 includes R1436Q and assigns REVEL class Likely-benign with one benign in-silico result, but the custom POLE BP4 rule requires at least four benign results. The case REVEL score is 0.42, above the generic BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used because a clean or adverse splice prediction cannot establish BP4 for a missense variant.

Rule

For a missense variant, use REVEL only. The POLE custom BP4 rule requires exact presence in Supplementary Table S2 or S3, a Likely-benign REVEL class, and >=4 benign in-silico results; otherwise generic REVEL BP4 supporting requires <=0.29.

Evidence considered

• Case REVEL score is 0.42; the published generic BP4 supporting threshold is <=0.29, from ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
• POLE PATH-250-323-s004.xlsx Supplementary Table S3 lists R1436Q as Likely-benign with one benign result among the in-silico tools; the POLE custom BP4 rule requires >=4 benign results.
• SpliceAI max delta 0.608 was not used because this missense variant must be adjudicated through the REVEL path, not the splice-impact path.

Still missing

• The exact variant was not found in PATH-250-323-s003.xlsx.txt under c.4307G>A, Arg1436Gln, or R1436Q; the applicable S004 entry was available.

Sources

Reasoning

BP6 is not met. The exact ClinVar record has zero expert-panel submissions. Although one ordinary single-submitter laboratory submission calls the variant Likely benign, ordinary laboratory submissions and aggregate ClinVar labels cannot trigger BP6 under the specified rule; no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.

Rule

BP6 applies only when the exact variant has a ClinVar expert-panel classification of Benign or Likely benign; none is present.

Evidence considered

• ClinVar variation 473660 exactly matches NM_006231.4:c.4307G>A (p.Arg1436Gln) and reports zero expert-panel submissions.
• One ordinary single-submitter laboratory submission reports Likely benign, while six report Uncertain significance; this non-expert assertion is excluded from BP6.
• The aggregate ClinVar label is conflicting classifications of pathogenicity and is not used as an expert-panel classification.

Sources

Reasoning

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected proband, with maternity and paternity confirmed for full-strength application. The available case evidence documents no proband-parent trio testing, parental genotypes, maternity/paternity confirmation, or documented de novo observation for NM_006231.4:c.4307G>A (POLE p.Arg1436Gln). Therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: confirmed de novo occurrence in an affected individual with confirmed maternity and paternity; without parental testing, PS2 is not established.

Evidence considered

• The governing POLE framework has no PS2 specification and therefore generic ACMG/AMP criteria were used.
• The case evidence contains no documented parental genotypes, trio analysis, maternity/paternity confirmation, or explicit de novo finding for this variant.

Still missing

• Affected proband phenotype and genotype documentation
• Maternal and paternal testing results
• Maternity and paternity confirmation
• Explicit de novo determination

Sources

Reasoning

The variant is missense, NM_006231.4:c.4307G>A (p.Arg1436Gln), but the available evidence contains no validated variant-specific functional assay demonstrating a damaging effect. The ClinVar evidence trail explicitly states that computational predictions had not been confirmed by functional assays, and the available POLE literature package provides no functional study for this variant. The local POLE framework customizes PM1, PS4, PP3, and BP4 only; it does not provide a POLE-specific PS3 rule or strength calibration. Therefore PS3 cannot be assessed rather than being inferred from in-silico prediction, somatic occurrence, or a submitter classification.

Evidence considered

• The exact ClinVar record for NM_006231.4:c.4307G>A (p.Arg1436Gln) includes a submission statement that five of seven in-silico tools predicted a deleterious effect, but that these predictions had not been confirmed by functional assays.
• No variant-specific functional assay, assay result, control description, or biological-effect measurement for p.Arg1436Gln is present in the supplied evidence.
• The POLE local framework is not an official CSPEC/VCEP specification and customizes PM1, PS4, PP3, and BP4; it contains no PS3 specification.
• Generic ACMG/AMP guidance requires functional evidence to be interpreted according to assay validity, biological relevance, controls, and the direction and magnitude of the observed effect (PMID:25741868).

Still missing

• A validated variant-specific functional assay is needed, with appropriate wild-type, loss-of-function or disease-positive, and negative controls.
• The assay should measure a biologically relevant POLE function and establish a calibrated damaging threshold for p.Arg1436Gln.

Sources

Reasoning

PM5 requires an established pathogenic missense change at the same residue caused by a different nucleotide substitution. The supplied PM5 candidate artifact contains no same-residue candidates and explicitly states that classic PM5 semantics could not be safely confirmed. The reviewed POLE tables contain no alternate substitution at residue 1436 with an established pathogenic designation; the available R1436Q row is the queried substitution itself.

Rule

Generic PM5: a different pathogenic missense change at the same amino-acid residue; evidence was insufficient to assess this requirement.

Evidence considered

• pm5_candidates.json reports zero total candidates and zero same-residue candidates and instructs that PM5 not be applied from that artifact alone.
• PATH-250-323-s002.xlsx lists p.R1436Q but no different amino-acid substitution at residue 1436 with a pathogenic designation.
• No reviewed governing source provides a pathogenic alternate substitution at Arg1436.

Still missing

• A complete curated same-residue ClinVar comparator search was not available in pm5_candidates.json.
• PATH-250-323-s001.tif full text is unavailable and could not be searched for an alternate residue-1436 substitution.

Sources

Reasoning

Generic ACMG/AMP PM6 concerns a presumed de novo variant in an affected individual when maternity and/or paternity is not confirmed. The available case evidence provides no affected-proband case description linked to this variant and no parental testing or explicit presumed-de novo observation. PM6 therefore cannot be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in an affected individual without confirmed maternity and/or paternity; an explicit case observation is required.

Evidence considered

• The governing POLE framework has no PM6 specification and therefore generic ACMG/AMP criteria were used.
• The case evidence does not document a presumed de novo occurrence, parental testing, or an affected individual with this variant.

Still missing

• Affected proband phenotype and genotype documentation
• Parental testing or a documented presumed-de-novo determination
• Case-level report identifying the variant in the affected individual

Sources

Reasoning

Generic ACMG/AMP PP1 requires co-segregation of the variant with disease in affected family members, with strength dependent on the number and informativeness of meioses. The available evidence contains no affected relatives, informative meioses, pedigree, or segregation testing for POLE c.4307G>A. PP1 cannot be assessed.

Rule

Generic ACMG/AMP PP1: co-segregation with disease in affected family members; strength must reflect the number and informativeness of observed meioses.

Evidence considered

• The governing POLE framework has no PP1 specification and therefore generic ACMG/AMP criteria were used.
• No affected-relative genotypes, co-segregation observations, pedigree, or informative meiosis count is available in the case evidence.

Still missing

• Pedigree and family structure
• Genotypes of affected relatives
• Number of informative meioses
• Phenotype assessments for relatives

Sources

Reasoning

PP2 requires a documented gene-level pattern in which missense variation is a common disease mechanism and benign missense variation is relatively uncommon. The reviewed POLE-specific framework does not specify PP2, and the supplied evidence does not provide a validated POLE missense-mechanism calibration or a quantitative benign-missense comparison suitable for this criterion. The paper's somatic exonuclease-domain findings cannot be converted into a germline PP2 assignment.

Rule

Generic PP2: missense variation is a common disease mechanism and benign missense variation is relatively uncommon; no qualifying POLE calibration was available.

Evidence considered

• The local POLE framework customizes PM1, PS4, PP3, and BP4, but does not specify PP2.
• PATH-250-323.pdf concerns somatic POLE exonuclease-domain mutations in endometrial carcinoma and does not establish the germline gene-level missense-mechanism evidence required for PP2.

Still missing

• No applicable POLE-specific PP2 rule or missense constraint calibration was supplied.
• No quantitative benign-missense comparison for POLE was available in the reviewed case evidence.

Sources

Reasoning

PP4 cannot be assessed because the available records do not establish a highly specific phenotype in the evaluated individual that is characteristic of a POLE-related disorder. ClinVar lists heterogeneous condition labels and the available OncoKB result is gene-level rather than variant-specific; neither supplies a documented phenotype match for this case.

Rule

Generic PP4: a highly specific phenotype or family history should support the disease association; no applicable POLE-specific PP4 rule or case-specific phenotype is available.

Evidence considered

• ClinVar reports heterogeneous condition labels for the exact variant but no case-specific phenotype evidence; the record has no expert-panel classification.
• OncoKB provides gene-level POLE context and identifies no variant-specific reviewed functional evidence; it does not establish a specific patient phenotype.

Still missing

• No detailed patient phenotype, diagnostic criteria, or phenotype-to-disease match is available.
• ClinVar condition labels are heterogeneous and do not provide a case-specific phenotype assessment.

Sources

Reasoning

BS2 cannot be assessed from the available population data. gnomAD v4.1 reports zero homozygotes, and the available records do not establish that any carriers are healthy adults or provide phenotype and penetrance information. Therefore, the data do not satisfy the BS2 requirement for observation in healthy individuals, but absence of homozygotes is not itself a definitive negative BS2 finding.

Rule

BS2 requires observation in healthy adults, including homozygous observation for a recessive condition or heterozygous observation for a dominant condition; no applicable POLE-specific BS2 rule is provided.

Evidence considered

• gnomAD v2.1 reports 0 homozygotes among 251204 alleles, and gnomAD v4.1 reports 0 homozygotes among 1613988 alleles.
• Population allele-frequency records do not document individual clinical phenotype, age, health status, penetrance, or disease ascertainment sufficiently to apply BS2.

Still missing

• No phenotype-confirmed healthy adult carrier or homozygote observations are available to evaluate BS2.
• No disease penetrance or prevalence information is available to determine whether observed carriers would be expected to be unaffected.

Sources

Reasoning

The variant is missense, NM_006231.4:c.4307G>A (p.Arg1436Gln), but the available evidence contains no validated variant-specific functional assay demonstrating a normal or benign effect. No assay controls, biologically relevant readout, quantitative result, or benign calibration threshold is available. The ClinVar evidence trail instead reports that computational predictions had not been confirmed by functional assays, and the local POLE framework does not specify BS3. Therefore BS3 cannot be assessed and cannot be assigned from the absence of reported functional evidence or from computational data.

Evidence considered

• The exact ClinVar record for NM_006231.4:c.4307G>A (p.Arg1436Gln) states that available computational predictions had not been confirmed by functional assays; this does not establish a normal functional result.
• No variant-specific functional assay, assay controls, biologically relevant readout, quantitative result, or benign calibration threshold for p.Arg1436Gln is present in the supplied evidence.
• The POLE local framework is not an official CSPEC/VCEP specification and customizes PM1, PS4, PP3, and BP4; it contains no BS3 specification.
• Generic ACMG/AMP guidance requires functional evidence to be interpreted according to assay validity, biological relevance, controls, and the direction and magnitude of the observed effect (PMID:25741868).

Still missing

• A validated variant-specific functional assay is needed to demonstrate preserved POLE function.
• The assay should include appropriate wild-type and disease-relevant controls plus a prespecified benign-effect threshold.

Sources

Reasoning

Generic ACMG/AMP BS4 requires lack of co-segregation in an affected family, supported by appropriate phenotype assessment and informative relatives. One ClinVar submission signal states that the variant was observed in an individual with breast cancer and an unaffected brother, but provides no verifiable family-level genotype details, phenotype evaluation, publication, or testing methodology. This is insufficient to establish BS4, so the criterion is not assessed rather than called not met.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected family members, requiring an informative family and reliable phenotype and genotype assessment.

Evidence considered

• A ClinVar submission signal reports the variant in an individual with breast cancer and also in an unaffected brother, but the supplied record does not provide a primary publication or auditable family-level testing details.
• The governing POLE framework has no BS4 specification and therefore generic ACMG/AMP criteria were used.
• The available information does not establish whether the unaffected brother was appropriately phenotyped, whether the genotype was confirmed, or whether the family was informative for non-segregation.

Still missing

• Primary family-level report or source
• Confirmed genotype of the unaffected relative
• Validated phenotype assessment and age-related penetrance information
• Testing methodology and relationship documentation

Sources

Reasoning

BP1 requires a gene-level context in which truncating or other variant classes, rather than missense variants, are the established disease mechanism. The reviewed POLE framework does not specify BP1, and the supplied materials do not establish a validated POLE disease mechanism that would make missense variants generally benign. Somatic recurrence and exonuclease-domain observations in endometrial carcinoma are not sufficient to apply germline BP1.

Rule

Generic BP1: missense variants are less likely pathogenic when the gene's established disease mechanism is predominantly truncating or another non-missense mechanism; no qualifying POLE evidence was available.

Evidence considered

• The local POLE framework does not specify BP1.
• PATH-250-323.pdf evaluates somatic POLE mutations and does not establish that germline POLE disease is predominantly caused by truncating or other non-missense variants.

Still missing

• No applicable POLE-specific BP1 rule or gene-level mechanism calibration was supplied.
• The reviewed somatic POLE paper does not establish the germline mechanism required for BP1.

Sources

Reasoning

BP2 requires the evaluated variant to be observed in trans with a pathogenic variant for a recessive disorder or in cis with a pathogenic variant for a dominant disorder, typically in an affected individual or relevant family context. The case materials document no affected-proband co-occurrence, second pathogenic variant, cis/trans phase, or inheritance result for NM_006231.4:c.4307G>A (p.Arg1436Gln), so BP2 cannot be assessed.

Rule

BP2 requires documented co-occurrence with a pathogenic or likely pathogenic variant and appropriate cis/trans phase; absence of those observations is insufficient to apply the criterion.

Evidence considered

• Generic ACMG/AMP guidance defines BP2 using a pathogenic variant in cis or trans, with interpretation dependent on inheritance mode and phase.
• The available case evidence contains no affected-proband co-occurrence report, second pathogenic or likely pathogenic variant, cis/trans phase determination, or family segregation result for NM_006231.4:c.4307G>A (p.Arg1436Gln).

Still missing

• Affected-proband genotype data showing a second pathogenic variant and its cis/trans phase are unavailable.
• Family-based inheritance or phasing results are unavailable.

Sources

Reasoning

BP5 cannot be assessed because no reliable evidence documents a pathogenic alternative molecular diagnosis explaining the relevant phenotype in this case. The available ClinVar record contains heterogeneous conditions but no validated alternative diagnosis or co-occurrence analysis, and the available cancer database context is not sufficient for BP5.

Rule

BP5 requires a pathogenic variant in another gene or an alternative molecular diagnosis that explains the phenotype; no such case-specific evidence is available.

Evidence considered

• ClinVar provides heterogeneous condition labels for the exact variant but does not document an alternative pathogenic molecular diagnosis for this case.
• No case-level co-occurrence or molecular-diagnostic evidence sufficient to apply BP5 is available.

Still missing

• No case-specific alternative pathogenic variant or molecular diagnosis is available.
• No validated co-occurrence analysis demonstrates that another variant explains the phenotype.

Sources