POLE c.1231G>T, p.Val411Leu

Reasoning

PS1 is met because the queried missense variant is NM_006231.4:c.1231G>T, p.Val411Leu/p.V411L, and an alternate nucleotide change at the same codon, NM_006231.3:c.1231G>C, was reported as p.(Val411Leu) in a germline case. The governing POLE framework identifies p.V411L as one of the established pathogenic exonuclease-domain hotspot substitutions. This is an exonic missense substitution, and the case's SpliceAI maximum delta score is 0.028, providing no substantial splice-impact concern for applying the protein-level same-amino-acid evidence.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.

Evidence considered

• León-Castillo et al. 2020, PATH-250-323.pdf: the paper states that the five common POLE exonuclease-domain mutations, including V411L, had confirmed pathogenicity in the somatic POLE-ultramutated context.
• PMID:27573199: the case report describes NM_006231.3:c.1231G>C as p.(Val411Leu), an alternate nucleotide change producing the same amino-acid substitution as the queried NM_006231.4:c.1231G>T.
• SpliceAI case result: maximum delta score 0.028 for the exonic missense variant.

Sources

Reasoning

PS3 is met at Supporting strength. PMID:25228659 reports variant-specific testing of recombinant human POLE containing V411L, with reduced 3′-5′ exonuclease activity relative to wild type and increased mutation frequency in a lacZ forward-mutation assay. These are biologically relevant functional readouts with wild-type comparison and support impaired proofreading. However, the evidence is not calibrated above Supporting because the supplied record does not establish clinical diagnostic-laboratory validation or reproducibility, and PMID:29352080 found discordant results in a chromosomal yeast model: no significant CanR increase and only a marginal His+ reversion increase for the analogous pol2-V426L allele. The human in-vitro result is therefore supportive of a damaging effect, but assay-system discordance and limited validation prevent a stronger designation.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• PMID:25228659: Recombinant human POLE N-terminal catalytic-subunit construct containing the exonuclease and DNA-synthesis domains was tested against wild type; V411L reduced 3′-5′ exonuclease activity without abolishing it and increased mutation frequency in a lacZ forward-mutation assay.
• PMID:29352080: The analogous chromosomal Saccharomyces cerevisiae pol2-V426L allele showed no significant CanR mutation increase and only a marginal His+ reversion increase, while the paper reports approximately threefold reduced human Polε-V411L exonuclease activity from in-vitro work.
• The functional evidence is biologically relevant and variant-specific, but the supplied studies do not establish clinical diagnostic-laboratory validation, reproducibility, or fully concordant results across model systems.

Still missing

• No supplied evidence demonstrates validation and reproducibility in a clinical diagnostic laboratory setting.
• The yeast model produced weak or non-significant mutator effects, requiring human review of assay-system discordance.

Sources

Reasoning

The governing POLE framework states: "Apply PS4_Supporting only when the exact POLE missense variant is recurrent in both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1, has a combined EC count >=10, and belongs to the established/pathogenic set highlighted by León-Castillo et al. 2020. Under the current package this supports p.P286R, p.V411L, p.A456P, and p.S297F. Do not upgrade above Supporting because the evidence source is somatic recurrence context rather than germline case-control evidence." The exact variant is listed as p.V411L/c.1231G>T in PATH-250-323-s002.xlsx with 101 COSMIC EC cases, 13 TCGA EC cases, and 114 combined cases; therefore the governing conditions are satisfied. The main paper independently identifies V411L as one of the five established pathogenic POLE exonuclease-domain hotspots and reports V411L in recurrent ultramutated endometrial tumors. This is somatic recurrence evidence, not a germline affected-versus-unaffected case-control study, so the framework caps PS4 at Supporting. The literature packet's ai_classified_papers list is empty; the variant-specific paper extracts were checked directly and do not provide an unaffected-control comparison or an odds ratio.

VCEP rule

Apply PS4_Supporting only when the exact POLE missense variant is recurrent in both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1, has a combined EC count >=10, and belongs to the established/pathogenic set highlighted by León-Castillo et al. 2020. Under the current package this supports p.P286R, p.V411L, p.A456P, and p.S297F. Do not upgrade above Supporting because the evidence source is somatic recurrence context rather than germline case-control evidence.

Evidence considered

• León-Castillo et al. 2020 Supplementary Table S1 (PATH-250-323-s002.xlsx), row p.V411L / c.1231G>T: COSMIC EC=101, TCGA EC=13, total=114; the exact variant is recurrent in both cohorts and total 114 >= 10.
• León-Castillo et al. 2020 main paper (PATH-250-323.pdf): V411L is one of the five established pathogenic POLE exonuclease-domain hotspot mutations; the paper reports recurrent V411L in ultramutated endometrial tumors.
• PMID:23636398, Results, Exome sequence analysis: the exact Val411Leu hotspot was present in 13 (76%) of 17 ultramutated endometrial samples.
• PMID:27573199, abstract and Results: p.(Val411Leu) was reported in one germline case and had previously been found as a recurrent somatic mutation; the paper is a single-patient report and supplies no unaffected comparator count.
• The literature_pass.json packet contains no ai_classified_papers; no reviewed source supplied germline case/control counts suitable for an odds-ratio calculation.

Still missing

• PATH-250-323-s001.tif was unavailable for text conversion and was not independently reviewed visually.
• No germline affected-versus-unaffected control counts or odds ratio were identified in the reviewed variant-specific literature.

Sources

Reasoning

PM1_Strong is met under the León-Castillo et al. 2020 custom POLE framework. The framework explicitly assigns PM1_Strong to the five established POLE exonuclease-domain hotspot missense variants, including p.V411L. The queried variant is p.V411L (Val411Leu); Supplementary Table S1 lists p.V411L/c.1231G>T with 101 COSMIC endometrial carcinoma cases, 13 TCGA cases, and 114 total cases. The required authoritative domain_tables entry is absent for POLE, so there is no additional domain-table list to check; the governing exact-hotspot rule itself is decisive. The supplementary figure PATH-250-323-s001.tif was unavailable as searchable text and was not used to infer absence of evidence.

VCEP rule

Apply PM1_Strong to the five established POLE exonuclease-domain hotspot missense variants emphasized by León-Castillo et al. 2020: p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F. These are the exact hotspot substitutions repeatedly treated in the paper as pathogenic for the POLE-ultramutated phenotype in endometrial carcinoma.

Evidence considered

• vcep_materials.json PM1 rule: Apply PM1_Strong to the five established POLE exonuclease-domain hotspot missense variants emphasized by León-Castillo et al. 2020, including p.V411L.
• León-Castillo et al. 2020 Supplementary Table S1, row p.V411L / c.1231G>T: 101 EC cases in COSMIC, 13 in TCGA, total 114.
• PATH-250-323.pdf: V411L is among the five common POLE exonuclease-domain mutations with confirmed pathogenicity in the paper's somatic ultramutation framework.
• vcep_materials.json domain_tables: no POLE domain_tables entry was present.

Still missing

• PATH-250-323-s001.tif was unavailable for text conversion and was not independently reviewed visually.

Sources

Reasoning

PM2 is met at Supporting strength. NM_006231.4:c.1231G>T (POLE p.Val411Leu) was absent from gnomAD v2.1 and gnomAD v4.1, and the available gnomAD v2.1 non-cancer and v3.1 non-cancer queries were also absent. No VCEP population-source restriction was provided, so the default all-comers gnomAD sources were used. The absence is compatible with the generic PM2 supporting threshold of <=0.0001, although the records provide no numerical FAF or allele-count estimate because the variant was not observed.

Rule

PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v2.1 all-comers query: absent from the dataset.
• gnomAD v4.1 all-comers query: absent from the dataset.
• GNOMAD_V2_1_NON_CANCER query: absent from the non-cancer dataset; the bundle specifies that this source is represented by exomes-only figures when present.
• GNOMAD_V3_1_NON_CANCER query: absent from the non-cancer dataset; the bundle specifies genomes-only for v3.1 because v3 has no exome cohort.
• No governing VCEP or CSPEC population rule requiring a different source was available; therefore the default all-comers gnomAD sources were retained.

Sources

Reasoning

The case report describes a patient with polyposis and rectosigmoid carcinoma, reports the p.Val411Leu germline variant absent in the healthy mother, and states that the father was unavailable for testing. This supports an assumed de novo event without complete parental confirmation, consistent with PM6. However, the report uses NM_006231.3:c.1231G>C rather than the requested NM_006231.4:c.1231G>T; the shared p.Val411Leu consequence supports but does not establish exact nucleotide-level identity.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• The patient had polyposis and rectosigmoid carcinoma, a phenotype reported in the context of POLE proofreading-associated polyposis.
• The p.Val411Leu germline variant was absent in the healthy mother.
• The father was unavailable for testing, so complete parental confirmation was not available.
• The report uses NM_006231.3:c.1231G>C, whereas this case concerns NM_006231.4:c.1231G>T; both are reported to encode p.Val411Leu.

Still missing

• Paternity was not tested or confirmed.
• The cited report's nucleotide notation differs from the requested variant, requiring confirmation that the reported p.Val411Leu allele is the same nucleotide-level variant.

Sources

Reasoning

The reported patient had polyposis and rectosigmoid carcinoma, and the variant was reported absent in the healthy mother, but the father was unavailable for testing. Therefore, both maternity and paternity were not confirmed, so the PS2 definition is not satisfied. The report also gives NM_006231.3:c.1231G>C rather than the requested NM_006231.4:c.1231G>T, although both encode p.Val411Leu; this identity discrepancy further limits use of the report for exact-variant PS2.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• A 14-year-old boy with polyposis and rectosigmoid carcinoma was reported with a heterozygous germline POLE p.(Val411Leu) variant.
• The variant was absent in the healthy mother; the father was unavailable for testing.
• The report's supplied coding notation is NM_006231.3:c.1231G>C, which differs from the requested NM_006231.4:c.1231G>T, although the protein change is p.Val411Leu.

Still missing

• Confirmed paternity is unavailable.
• The cited report uses NM_006231.3:c.1231G>C rather than the requested NM_006231.4:c.1231G>T, despite the same p.Val411Leu protein change.

Sources

Reasoning

This is a missense variant, so the POLE missense-specific PP3 rule is the governing scope. The exact variant was not found in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx under c.1231G>T, p.Val411Leu, or p.V411L; therefore the custom table trigger is unavailable and the rule directs fallback to the generic in-silico workflow. Under that fallback, missense variants use REVEL only, and REVEL 0.457 lies in the defined [0.250, 0.750] gray zone, so PP3 is not met. The main PATH-250-323.pdf contains contextual V411L/c.1231G>T/C material, but it is not a PP3 pre-assignment and does not alter the fallback result.

VCEP rule

Apply PP3_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'likely disease causing' (including minor spelling variants), and the number of benign in silico results is <=1. If the variant is absent from the supplementary tables, do not use this custom PP3 rule and fall back to the project's generic in-silico workflow.

Evidence considered

• PATH-250-323.pdf full-text table row for V411L: c.1231G>T/C, 1 benign result by in-silico tools, POLE-score 4–6, and recurrent status; this is contextual exact-variant material rather than a PP3 pre-assigned code.
• PATH-250-323-s003.xlsx searched for c.1231G>T, p.Val411Leu, and p.V411L; no exact-variant entry was found.
• PATH-250-323-s004.xlsx searched for c.1231G>T, p.Val411Leu, and p.V411L; no exact-variant entry was found.
• The case predictor result is REVEL score 0.457. The generic missense fallback defines REVEL values from 0.250 through 0.750 as the gray zone, producing neither PP3 nor BP4.

Still missing

• No exact-variant entry was found in PATH-250-323-s003.xlsx after searching c.1231G>T, p.Val411Leu, and p.V411L.
• No exact-variant entry was found in PATH-250-323-s004.xlsx after searching c.1231G>T, p.Val411Leu, and p.V411L.

Sources

Reasoning

The generic rule requires a reputable source to report the exact variant as pathogenic while the evidence is unavailable for independent evaluation. The exact ClinVar record reports Uncertain significance from two ordinary clinical-laboratory submissions, with no expert-panel classification; the reviewed literature reports recurrence and functional or case observations but does not constitute an inaccessible reputable-source pathogenic assertion for this exact germline classification. Therefore PP5 is not met.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 376503 for NM_006231.4:c.1231G>T (p.Val411Leu): classification Uncertain significance, review status criteria provided/multiple submitters/no conflicts, two clinical-laboratory submissions, and no expert-panel entry.
• The reviewed paper extracts describe somatic recurrence, functional findings, or a single germline case; none supplies an exact-variant ClinVar expert-panel pathogenic or likely-pathogenic classification.

Sources

Reasoning

BA1 is not met. NM_006231.4:c.1231G>T (POLE p.Val411Leu) was absent from gnomAD v2.1 and gnomAD v4.1, including the available non-cancer subset queries; therefore no allele frequency, filtering grpmax FAF, or qualifying population allele count reaches the >=0.05 stand-alone benign threshold. The variant is also not assigned a pathogenic ClinVar consensus that would create the high-frequency pathogenic-allele caveat, although the absent population data independently exclude BA1.

Rule

BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v2.1 all-comers query: NM_006231.4:c.1231G>T / GRCh37 12-133250289-C-A was absent; no allele count or filtering grpmax FAF was reported.
• gnomAD v4.1 all-comers query: GRCh38 12-132673703-C-A was absent; no allele count or filtering grpmax FAF was reported.
• The available GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER queries were also absent; no VCEP-specific population source was present, so the default all-comers sources were used.
• ClinVar record 376503 reports Uncertain significance from two clinical laboratories, not a pathogenic consensus; this does not override the absent population finding.

Sources

Reasoning

BS1 is not met. The variant was absent from gnomAD v2.1 and gnomAD v4.1, as well as the available non-cancer subset queries, so its observed frequency is not greater than expected for POLE-associated disease and cannot meet the generic >=0.01 default. No ancestry-specific elevation, founder signal, filtering grpmax FAF, or allele count is available that would require a maximum-credible-frequency analysis under Whiffin et al. 2017.

Rule

BS1: Allele frequency is greater than expected for the disorder.

Evidence considered

• gnomAD v2.1 all-comers query was absent, with no reported allele frequency, filtering grpmax FAF, ancestry-specific frequency, or observed allele count.
• gnomAD v4.1 all-comers query was absent, with no reported allele frequency, filtering grpmax FAF, ancestry-specific frequency, or observed allele count.
• The available GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER queries were also absent; no elevated ancestry-specific frequency was identified.
• The generic BS1 default is >=0.01, but no maximum-credible-frequency calculation is needed because the variant has no observed population frequency in the available datasets; Whiffin et al. 2017 (PMID:28518168) is the applicable maximum-credible-frequency reference if a future ancestry-specific frequency is found.

Sources

Reasoning

BS3 is not met. The available variant-specific functional evidence does not show no damaging effect: recombinant human POLE V411L reduced 3′-5′ exonuclease activity and increased mutation frequency relative to wild type in PMID:25228659, while the yeast study in PMID:29352080 was weak or discordant rather than a well-established demonstration of normal protein function or splicing. The absence of a benign functional result means BS3 cannot be applied.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• PMID:25228659: Variant-specific human assays showed reduced V411L exonuclease activity and increased mutation frequency compared with wild-type POLE, contradicting a no-damaging-effect interpretation.
• PMID:29352080: The analogous yeast allele showed weak or non-significant mutator effects, but this isolated model result does not establish normal protein function and conflicts with the human biochemical evidence.

Sources

Reasoning

This is a missense variant, so the POLE missense-specific BP4 rule is the governing scope. The exact variant was not found in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx under c.1231G>T, p.Val411Leu, or p.V411L; therefore the custom table trigger is unavailable and the rule directs fallback to the generic in-silico workflow. Under that fallback, missense variants use REVEL only, and REVEL 0.457 lies in the defined [0.250, 0.750] gray zone, so BP4 is not met. SpliceAI is not used for this missense determination. The main PATH-250-323.pdf contains contextual V411L/c.1231G>T/C material, but it is not a BP4 pre-assignment and does not alter the fallback result.

VCEP rule

Apply BP4_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'Likely benign' or 'Likely-benign', and the number of benign in silico results is >=4. If the variant is absent from the supplementary tables, do not use this custom BP4 rule and fall back to the project's generic in-silico workflow.

Evidence considered

• PATH-250-323.pdf full-text table row for V411L: c.1231G>T/C, 1 benign result by in-silico tools, POLE-score 4–6, and recurrent status; this is contextual exact-variant material rather than a BP4 pre-assigned code.
• PATH-250-323-s003.xlsx searched for c.1231G>T, p.Val411Leu, and p.V411L; no exact-variant entry was found.
• PATH-250-323-s004.xlsx searched for c.1231G>T, p.Val411Leu, and p.V411L; no exact-variant entry was found.
• The case predictor result is REVEL score 0.457. The generic missense fallback defines REVEL values below 0.250 as BP4; 0.457 is in the gray zone, so BP4 is not met. SpliceAI max delta 0.028 is not used for a missense BP4 assessment.

Still missing

• No exact-variant entry was found in PATH-250-323-s003.xlsx after searching c.1231G>T, p.Val411Leu, and p.V411L.
• No exact-variant entry was found in PATH-250-323-s004.xlsx after searching c.1231G>T, p.Val411Leu, and p.V411L.

Sources

Reasoning

The generic rule requires a reputable source to report the exact variant as benign while the evidence is unavailable for independent evaluation. The exact ClinVar record contains only two ordinary clinical-laboratory Uncertain significance submissions and no expert-panel benign or likely-benign classification. BP6 is therefore not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 376503 for NM_006231.4:c.1231G>T (p.Val411Leu): Uncertain significance, two clinical-laboratory submissions, and no expert-panel entry; ordinary submissions and aggregate labels do not satisfy BP6.

Sources

Reasoning

PM3 cannot be assessed from the available evidence. The relevant report describes p.(Val411Leu) as a heterozygous germline finding in one affected boy, with the healthy mother negative and the father unavailable for testing; it does not establish a pathogenic variant in trans, parental phase, or that the evaluated POLE disorder should be treated as recessive. No affected-proband series with confirmed trans pathogenic alleles is provided.

Rule

For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.

Evidence considered

• PMID:27573199: The report describes p.(Val411Leu) as a heterozygous germline mutation in a 14-year-old boy with polyposis and rectosigmoid carcinoma; the mutation was absent in the healthy mother and the father was unavailable for testing. It does not report a second pathogenic allele or confirmed trans phase.

Still missing

• Disease inheritance mode must be established for this interpretation.
• A second pathogenic variant and confirmed trans phase in an affected individual are not documented.
• Parental testing is incomplete because the father was unavailable.

Sources

Reasoning

PM5 cannot be assessed because no different missense substitution at residue Val411 with an independently established pathogenic classification was identified in the available evidence. The reported NM_006231.3:c.1231G>C variant is an alternate nucleotide change producing the same p.Val411Leu amino-acid change, so it supports PS1 rather than PM5. No qualifying same-residue comparator is listed in pm5_candidates.json.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.

Evidence considered

• pm5_candidates.json: zero same-residue candidates were identified and classic PM5 eligibility could not be confirmed.
• PMID:27573199: NM_006231.3:c.1231G>C is an alternate nucleotide change for the same p.Val411Leu amino-acid substitution, not a different missense substitution at Val411.

Still missing

• A qualifying independently established pathogenic missense comparator at residue Val411 is not available in the reviewed evidence.

Sources

Reasoning

The available case report describes a single affected patient and does not report multiple affected family members, informative meioses, or cosegregation of the variant with disease. PP1 therefore cannot be assessed.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• The available report is a single-patient case report and provides no reported affected relatives or cosegregation analysis.

Still missing

• No family segregation data or additional affected relatives were reported.

Sources

Reasoning

PP2 cannot be assessed because the available evidence does not provide the required gene-level demonstration that POLE has both a low rate of benign missense variation and missense variation as a common disease mechanism under the generic rule. The absence of this specific paired evidence prevents a supported PP2 decision.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Still missing

• No qualifying gene-level benign-missense-rate and missense-mechanism evidence was available for the PP2 rule.

Reasoning

The available case materials do not provide the current patient's phenotype or family history in sufficient detail to determine whether it is highly specific for a disease with a single genetic etiology. The germline POLE case report describes another patient with polyposis and rectosigmoid carcinoma, but that published phenotype cannot be transferred to the present case.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Still missing

• Current patient phenotype and family history suitable for PP4 assessment are not available.

Reasoning

BS2 cannot be assessed from the available evidence. gnomAD absence documents no observed population occurrence but does not document an unaffected healthy adult carrying the variant in the required zygosity. No healthy-adult heterozygote, homozygote, or hemizygote observation, age, phenotype, penetrance context, or inheritance-specific evidence was provided.

Rule

BS2: Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• gnomAD v2.1 and v4.1 reported the variant as absent; these negative population queries do not establish an unaffected carrier observation and do not provide individual-level phenotype or age data.
• No source in the case evidence documents a healthy adult heterozygote, homozygote, or hemizygote for this POLE variant.

Still missing

• A documented unaffected healthy adult observation with disease-relevant zygosity, age, phenotype, and penetrance context is needed.

Sources

Reasoning

No affected family members with documented absence of the variant were reported. The healthy mother's negative test is not evidence of lack of segregation in an affected member, so BS4 cannot be assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The report identifies the mother as healthy and variant-negative; it does not describe any affected relative who tested negative for the variant.

Still missing

• No affected relatives with variant-negative testing were reported.

Sources

Reasoning

BP1 cannot be assessed because the available evidence does not establish that POLE is a gene for which primarily truncating variants, rather than missense variants, are known to cause disease. The reviewed POLE material instead focuses on missense exonuclease-domain variants, but that observation alone does not satisfy or refute the generic BP1 gene-level rule.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Still missing

• No qualifying gene-level disease-mechanism evidence was available to determine whether truncating variants primarily cause POLE-associated disease.

Reasoning

BP2 cannot be assessed from the available evidence. The relevant report documents a heterozygous germline p.(Val411Leu) finding in one affected boy, but provides no pathogenic variant reported in trans, no cis-phase result with another pathogenic variant, and no molecular phasing data. The available case therefore does not establish either BP2 pathway.

Rule

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

• PMID:27573199: The report describes a heterozygous germline p.(Val411Leu) finding in one affected boy and incomplete parental testing, but does not document another pathogenic variant or cis/trans phase.

Still missing

• Testing for an additional pathogenic variant is not documented.
• Cis/trans phase is not established.
• The inheritance and penetrance context required for the trans pathway is not documented.

Sources

Reasoning

The available materials do not document that the current patient has an alternate molecular basis for disease. Somatic POLE recurrence and the published single germline case do not establish an alternate molecular diagnosis in this case.

Rule

Variant found in a case with an alternate molecular basis for disease.

Still missing

• Current patient's diagnostic phenotype and independent molecular findings were not provided.