POLE c.2299G>A, p.Glu767Lys

Reasoning

PM2 Supporting is met. No governing VCEP or criterion-specific specification requires a non-cancer or exome-only source for this criterion, so the default all-comers gnomAD entries were used. gnomAD v4.1 contains the variant at AF 6.81503e-06 (11/1,614,080 alleles), with 0 homozygotes and grpmax FAF 3.59e-06; this is below the supplied PM2 Supporting threshold of <=0.0001. gnomAD v2.1 also reports absence, while the explicitly available non-cancer subsets report absence but do not change the default-source decision. The result is extremely rare rather than strictly absent in the default combined dataset.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• gnomAD v4.1: AF 6.81503e-06 (11/1,614,080 alleles), homozygotes 0, grpmax FAF 3.59e-06.
• gnomAD v2.1: absent from the queried dataset.
• The available non-cancer subset records also report absence, but no governing VCEP specifies non-cancer or exome-only sourcing for PM2 in this case; therefore the default all-comers gnomAD v2.1/v4.1 entries were used.
• Generic calibration supplied in the case: PM2 Supporting threshold <=0.0001, ClinGen SVI recommendation (PMID:25741868).

Sources

Reasoning

The governing León-Castillo custom POLE rule is: "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 NM_006231.4:c.2299G>A / p.Glu767Lys / p.E767K was not found in PATH-250-323.pdf or PATH-250-323-s002.xlsx, and the governing rule's listed qualifying variants do not include it. No germline case-control comparison was identified. PATH-250-323-s001.tif is unavailable for text search, so it cannot establish an exact-variant qualifying entry.

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 custom POLE framework: PS4_Supporting requires recurrence in both COSMIC and TCGA, combined EC count >=10, and membership in the established/pathogenic set; the explicitly supported variants are p.P286R, p.V411L, p.A456P, and p.S297F.
• PATH-250-323.pdf and PATH-250-323-s002.xlsx.txt were searched under all three variant notations: c.2299G>A, p.Glu767Lys, and p.E767K; no exact entry was found.
• The extracted case evidence reports COSMIC count n=1 and no statistically significant hotspot, but these generic somatic observations do not satisfy the custom rule's exact recurrent COSMIC-plus-TCGA and established-hotspot requirements.
• PATH-250-323-s001.tif is declared by the index but unavailable for conversion; no assumption was made about its contents.

Still missing

• No exact-variant entry found after searching PATH-250-323.pdf for c.2299G>A, p.Glu767Lys, and p.E767K.
• No exact-variant entry found after searching PATH-250-323-s002.xlsx.txt for c.2299G>A, p.Glu767Lys, and p.E767K.
• PATH-250-323-s001.tif was unavailable for conversion and visual review was not performed.
• No germline case-control counts or matched-ancestry case frequency were available for this variant.

Sources

Reasoning

The governing León-Castillo et al. 2020 custom POLE framework limits PM1 to exact substitutions in its listed hotspot, pathogenic non-hotspot, or uncertain recurrent exonuclease-domain sets. p.E767K is not one of the five strong-hotspot substitutions (p.P286R, p.V411L, p.S297F, p.A456P, p.S459F), the six moderate substitutions (p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, p.D368Y), or the four supporting substitutions (p.A465V, p.L424V, p.T278M, p.A428T). The variant was searched as c.2299G>A, p.Glu767Lys, and p.E767K in PATH-250-323.pdf and PATH-250-323-s002.xlsx with no matching entry. vcep_materials.json has no POLE domain_tables entry. The supplementary figure PATH-250-323-s001.tif has no converted full text and could not be independently searched.

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. ... Apply PM1_Moderate to the exact non-hotspot exonuclease-domain missense variants identified in the paper as recurrent and POLE-score >=4 / classified as pathogenic in the TCGA-based analysis: p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y. Use this only for these exact substitutions, not all substitutions at the same codon. ... Apply PM1_Supporting to exact recurrent exonuclease-domain missense variants that the paper places in the POLE-score 3 / uncertain tier rather than the pathogenic tier: p.A465V, p.L424V, p.T278M, and p.A428T. This captures hotspot/domain context without promoting them to the paper's pathogenic set.

Evidence considered

• León-Castillo et al. 2020 custom POLE framework: PM1_Strong is restricted to p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F; p.E767K is not listed.
• León-Castillo et al. 2020 custom POLE framework: PM1_Moderate is restricted to p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y; p.E767K is not listed.
• León-Castillo et al. 2020 custom POLE framework: PM1_Supporting is restricted to p.A465V, p.L424V, p.T278M, and p.A428T; p.E767K is not listed.
• PATH-250-323.pdf: searches for c.2299G>A, p.Glu767Lys, and p.E767K found no matching entry.
• PATH-250-323-s002.xlsx, Supplementary Table S1: searches for c.2299G>A, p.Glu767Lys, and p.E767K found no matching entry.
• PATH-250-323-s001.tif: full text unavailable because the supplementary figure could not be converted.

Still missing

• No entry for c.2299G>A, p.Glu767Lys, or p.E767K was found in PATH-250-323.pdf.
• No entry for c.2299G>A, p.Glu767Lys, or p.E767K was found in PATH-250-323-s002.xlsx.
• PATH-250-323-s001.tif was searched only for available converted text; full text is unavailable because the file could not be converted, so visual confirmation remains a gap.

Sources

Reasoning

The POLE custom PP3 rule applies to missense variants that appear in Supplementary Table S2 or S3, have REVEL class 'likely disease causing' (including minor spelling variants), and have no more than one benign in silico result. The variant NM_006231.4:c.2299G>A (p.Glu767Lys/p.E767K) was not found in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Under the framework's explicit fallback, the generic missense workflow uses REVEL only: REVEL is 0.352, which lies in the defined gray zone [0.250, 0.750], so PP3 is not met. SpliceAI max delta 0.003 is not used for a missense variant under that workflow, and BayesDel is not usable under the stated rules.

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

• The POLE framework's PP3 rule requires an exact Supplementary Table S2/S3 match, REVEL class 'likely disease causing', and <=1 benign in silico result.
• PATH-250-323-s003.xlsx, sheet 'Suplementary Table S2': no row matching c.2299G>A, p.Glu767Lys, or p.E767K was found.
• PATH-250-323-s004.xlsx, sheet 'Supplementary Table S3': no row matching c.2299G>A, p.Glu767Lys, or p.E767K was found.
• Generic missense fallback: REVEL 0.352; the defined PP3 threshold is >0.750, while scores from 0.250 through 0.750 are gray zone and support neither PP3 nor BP4.
• SpliceAI max delta is 0.003, but the generic rule specifies REVEL only for missense variants; BayesDel has no verified usable threshold.

Still missing

• No matching c.2299G>A, p.Glu767Lys, or p.E767K entry was found in PATH-250-323-s003.xlsx (Supplementary Table S2).
• No matching c.2299G>A, p.Glu767Lys, or p.E767K entry was found in PATH-250-323-s004.xlsx (Supplementary Table S3).

Sources

Reasoning

The governing generic rule is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." ClinVar variation 578063 contains two clinical-laboratory submissions, both Uncertain significance, with zero expert-panel submissions. The only reviewed paper linked through the literature packet (PMID:25394175) does not mention POLE or this variant and provides no variant-specific pathogenic report. Therefore the exact-variant expert-panel pathogenic/likely pathogenic requirement 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 578063 exactly matches NM_006231.4:c.2299G>A (p.Glu767Lys), but both submissions classify it as Uncertain significance and the audit records expert_panel_submissions=0.
• PMID:25394175 was checked in full text because literature_pass.json flagged it for PP5/PS4; it does not mention POLE, c.2299G>A, p.Glu767Lys, or p.E767K and contains no variant-specific pathogenic report.

Sources

Reasoning

BA1 is not met. The governing frequency metric is gnomAD v4.1 grpmax FAF, 3.59e-06, which is far below the generic stand-alone threshold of 0.05. The highest observed subpopulation point estimate is Ashkenazi Jewish AF 3.37747e-05 from 1/29,608 alleles; it is not used for BA1 because the required filtering allele frequency is below threshold. The variant has 0 homozygotes and is present at only 11/1,614,080 total alleles. No governing VCEP specifies a different population source, and no disease-specific high-frequency benign interpretation overrides this result.

Rule

Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v4.1: total AF 6.81503e-06 (11/1,614,080 alleles), homozygotes 0, grpmax FAF 3.59e-06; highest observed Ashkenazi Jewish AF 3.37747e-05 (1/29,608 alleles).
• Generic calibration supplied in the case: BA1 stand-alone threshold >=0.05, ACMG/AMP 2015 (PMID:25741868). The grpmax FAF, rather than the Ashkenazi Jewish popmax point estimate, is the applied metric.

Sources

Reasoning

BS1 is not met. gnomAD v4.1 grpmax FAF is 3.59e-06, below the supplied generic BS1 default threshold of 0.01, so the allele frequency is not greater than expected for the disorder on the available population evidence. The highest observed Ashkenazi Jewish point estimate, 3.37747e-05 from 1/29,608 alleles, is not substituted for grpmax FAF. Because the filtering frequency is already well below the generic threshold, no maximum-credible-frequency calculation is needed to reject BS1; there is no elevated ancestry-specific frequency requiring a reduced-penetrance or founder-allele exception.

Rule

Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• gnomAD v4.1: grpmax FAF 3.59e-06; highest observed Ashkenazi Jewish point estimate AF 3.37747e-05 from 1/29,608 alleles; total AF 6.81503e-06 from 11/1,614,080 alleles.
• Generic calibration supplied in the case: BS1 default threshold >=0.01, with maximum-credible-frequency context from Whiffin et al. 2017 (PMID:28518168). ClinGen SVI/Ghosh et al. 2018 guidance requires using filtering allele frequency rather than popmax point estimate and a population with at least 2,000 observed alleles.

Sources

Reasoning

The POLE custom BP4 rule applies to missense variants that appear in Supplementary Table S2 or S3, have REVEL class 'Likely benign' or 'Likely-benign', and have at least four benign in silico results. The variant NM_006231.4:c.2299G>A (p.Glu767Lys/p.E767K) was not found in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Under the framework's explicit fallback, the generic missense workflow uses REVEL only: REVEL is 0.352, which is not below the BP4 threshold of 0.250 and lies in the defined gray zone [0.250, 0.750], so BP4 is not met. SpliceAI max delta 0.003 is not used for a missense variant under that workflow, and BP4 is not assessed from the splice 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

• The POLE framework's BP4 rule requires an exact Supplementary Table S2/S3 match, REVEL class 'Likely benign' or 'Likely-benign', and >=4 benign in silico results.
• PATH-250-323-s003.xlsx, sheet 'Suplementary Table S2': no row matching c.2299G>A, p.Glu767Lys, or p.E767K was found.
• PATH-250-323-s004.xlsx, sheet 'Supplementary Table S3': no row matching c.2299G>A, p.Glu767Lys, or p.E767K was found.
• Generic missense fallback: REVEL 0.352; the defined BP4 threshold is <0.250, while scores from 0.250 through 0.750 are gray zone and support neither PP3 nor BP4.
• SpliceAI max delta is 0.003, but the generic rule specifies REVEL only for missense variants.

Still missing

• No matching c.2299G>A, p.Glu767Lys, or p.E767K entry was found in PATH-250-323-s003.xlsx (Supplementary Table S2).
• No matching c.2299G>A, p.Glu767Lys, or p.E767K entry was found in PATH-250-323-s004.xlsx (Supplementary Table S3).

Sources

Reasoning

The governing generic rule is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." ClinVar variation 578063 exactly matches the variant but has two Uncertain significance clinical-laboratory submissions and zero expert-panel submissions; no exact-variant expert-panel benign or likely benign classification is present. The reviewed PMID:25394175 also does not mention this variant.

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 578063 exactly matches NM_006231.4:c.2299G>A (p.Glu767Lys), but both submissions classify it as Uncertain significance and the audit records expert_panel_submissions=0.
• PMID:25394175 was reviewed in full text and does not mention POLE, c.2299G>A, p.Glu767Lys, or p.E767K.

Sources

Reasoning

The variant is NM_006231.4:c.2299G>A, p.Glu767Lys (p.E767K). No previously established pathogenic variant producing the same amino-acid change was identified in the reviewed case evidence. The available ClinVar records classify this exact variant as uncertain significance and do not establish a pathogenic same-amino-acid comparator. The evidence is therefore insufficient to determine PS1 rather than supporting a negative PS1 conclusion.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• The case evidence identifies the exact variant as NM_006231.4:c.2299G>A (p.Glu767Lys/p.E767K).
• ClinVar variation 578063 contains two submissions, both classifying the exact variant as uncertain significance; no pathogenic same-amino-acid comparator is established there.

Still missing

• A comprehensive search for previously established pathogenic variants with the same p.Glu767Lys amino-acid change outside the reviewed case sources was not available.

Reasoning

No case-specific evidence was supplied establishing the patient's disease phenotype, absence of family history, and confirmed maternity and paternity for NM_006231.4:c.2299G>A. Therefore, de novo status cannot be assessed.

Rule

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

Still missing

• Document the proband's disease phenotype and relevant clinical diagnosis.
• Document family history.
• Provide parental testing results confirming both maternity and paternity and showing the variant absent in both parents.

Reasoning

No variant-specific in vitro or in vivo functional study was identified for POLE NM_006231.4:c.2299G>A (p.Glu767Lys). OncoKB explicitly reported no variant-specific reviewed functional evidence, and the only fetched publication was not variant-specific and contained no POLE or p.Glu767Lys functional findings. Therefore, the evidence is insufficient to apply PS3 at any strength; absence of identified functional evidence is not evidence against function.

Rule

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

Evidence considered

• OncoKB states that it did not identify variant-specific reviewed functional evidence for POLE p.Glu767Lys.
• PMID:25394175 was checked; the supplied text does not mention POLE, c.2299G>A, or p.(E767K), and provides no relevant functional findings.

Still missing

• A validated, reproducible, biologically relevant functional assay directly testing POLE p.Glu767Lys is needed.

Sources

Reasoning

PM3 cannot be assessed because the available evidence does not establish that the relevant POLE disorder is recessive, does not identify a pathogenic partner variant, and provides no parental or offspring testing to determine whether this variant is in trans. No affected-proband observation with a confirmed pathogenic variant in trans is documented.

Rule

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

Evidence considered

• ClinVar variation 578063 contains two germline submissions for NM_006231.4:c.2299G>A (p.Glu767Lys), both classified as uncertain significance; the record provides no pathogenic partner variant, affected-proband allelic observation, or phase information.
• No supplied evidence documents parental or offspring testing, trans phase, or a recessive inheritance mode for the relevant POLE disorder.

Still missing

• Inheritance mode for the relevant POLE disorder is not documented.
• No pathogenic partner variant is identified.
• No parental or offspring testing establishes phase.
• No affected-proband allelic observation is documented.

Sources

Reasoning

The variant is p.Glu767Lys at residue 767. The reviewed VCEP files contain no entry for c.2299G>A, p.Glu767Lys, or p.E767K and the case evidence provides no established pathogenic alternate missense variant at residue 767. Because absence of a comparator in these sources does not prove that no pathogenic alternate residue-767 variant exists elsewhere, PM5 cannot be assessed conclusively.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The variant is p.Glu767Lys/p.E767K at POLE residue 767.
• PATH-250-323.pdf and PATH-250-323-s002.xlsx contained no exact queried-variant entry and no reviewed evidence established a pathogenic alternate missense change at residue 767.

Still missing

• A comprehensive residue-767 search for established pathogenic alternate missense variants outside the reviewed case sources was not available.

Reasoning

No case-specific evidence was supplied showing that NM_006231.4:c.2299G>A is de novo or documenting parental testing. The available materials do not establish assumed de novo status without confirmed maternity and paternity.

Rule

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

Still missing

• Provide evidence that the variant is absent from both tested parents or otherwise establish assumed de novo status.
• Document whether maternity and paternity were confirmed.

Reasoning

No affected relatives, genotype results, pedigree, phenotype assessments, or meioses were supplied. Consequently, co-segregation of NM_006231.4:c.2299G>A with disease in affected family members cannot be assessed.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.

Still missing

• Provide a pedigree identifying affected family members.
• Provide genotype and phenotype data for affected relatives and informative unaffected relatives.
• Provide the number of informative meioses and assess phenotype consistency.

Reasoning

The reviewed evidence does not establish both required gene-level facts for PP2: a low rate of benign missense variation and missense variation as a common disease mechanism in the relevant germline disease context. The León-Castillo source describes somatic POLE endometrial-carcinoma mutations and is not sufficient by itself to establish the generic germline PP2 conditions.

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.

Evidence considered

• The reviewed León-Castillo package concerns somatic POLE mutations in endometrial carcinoma and does not establish the generic germline PP2 prerequisites.

Still missing

• No validated gene-level assessment of benign missense constraint and germline missense disease mechanism was available for PP2.

Reasoning

The governing generic rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The available case evidence contains no patient phenotype or family-history description sufficient to assess phenotype specificity or a single genetic etiology.

Rule

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

Evidence considered

• No phenotype or family-history evidence sufficient for PP4 assessment was present in the reviewed case materials.

Still missing

• Patient phenotype and family history relevant to POLE-associated disease were not provided.

Reasoning

BS2 cannot be assessed from the available evidence. gnomAD v4.1 reports 11 heterozygous alleles and 0 homozygotes, but this aggregate population record does not identify an observed healthy adult individual, establish the relevant inheritance model, or demonstrate that full penetrance is expected at an early age. The case contains no qualifying individual-level healthy-adult observation or disease-specific penetrance evidence for POLE p.Glu767Lys.

Rule

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 v4.1 reports 11 total observed alleles, 0 homozygotes, and no individual-level phenotype or age information in the supplied record.

Still missing

• Individual-level observation of the variant in a phenotypically healthy adult
• Confirmed inheritance model and evidence that full penetrance is expected at an early age

Sources

Reasoning

No variant-specific in vitro or in vivo functional study was identified for POLE NM_006231.4:c.2299G>A (p.Glu767Lys) that demonstrates absence of a damaging effect on protein function or splicing. OncoKB reported no variant-specific reviewed functional evidence, and the only fetched publication contained no relevant POLE or p.Glu767Lys findings. Therefore, BS3 cannot be applied; lack of an assay is not a benign functional result.

Rule

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

Evidence considered

• OncoKB states that it did not identify variant-specific reviewed functional evidence for POLE p.Glu767Lys.
• PMID:25394175 was checked; the supplied text does not mention POLE, c.2299G>A, or p.(E767K), and provides no relevant functional findings.

Still missing

• A validated, reproducible, biologically relevant functional assay demonstrating preserved POLE protein function or splicing is needed.

Sources

Reasoning

No affected family members, familial genotypes, phenotype assessments, or pedigree information were supplied. Lack of segregation therefore cannot be established, and the phenocopy and multiple-pathogenic-variant caveats cannot be evaluated.

Rule

Lack of segregation in affected members of a family.

Still missing

• Provide a pedigree and identify affected relatives.
• Provide variant testing and phenotype data for affected relatives.
• Evaluate possible phenocopies and the possibility of more than one pathogenic variant in the family.

Reasoning

The reviewed evidence does not establish that POLE disease is caused primarily by truncating variants. The available León-Castillo source instead concerns recurrent somatic missense mutations, but that somatic context cannot by itself determine the generic germline BP1 gene-level mechanism. BP1 is therefore not assessed.

Rule

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

Evidence considered

• The reviewed León-Castillo package describes somatic POLE missense mutations but does not establish the generic germline BP1 prerequisite that disease is primarily caused by truncating variants.

Still missing

• No validated germline disease-mechanism review comparing truncating and missense pathogenic variants in POLE was available.

Reasoning

BP2 cannot be assessed because no pathogenic partner variant is identified and no family or affected-proband data establish either that this variant is in trans with a pathogenic variant or that it is in cis with a pathogenic variant.

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

• ClinVar variation 578063 contains two germline submissions for NM_006231.4:c.2299G>A (p.Glu767Lys), both classified as uncertain significance; the record provides no pathogenic partner variant or phase information.
• No supplied evidence documents a pathogenic variant in trans or cis with NM_006231.4:c.2299G>A.

Still missing

• No pathogenic partner variant is identified.
• No parental, offspring, or other phase testing establishes trans or cis configuration.
• No affected-proband observation is documented.

Sources

Reasoning

The governing generic rule is: "Variant found in a case with an alternate molecular basis for disease." The reviewed case materials provide no alternate molecular diagnosis, second pathogenic variant, or other molecular basis for the patient's disease, so BP5 cannot be assessed.

Rule

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

Evidence considered

• No alternate molecular basis for disease was documented in the reviewed case materials.

Still missing

• No alternate molecular diagnosis or competing pathogenic variant was provided.