POLD1 c.353C>T, p.(Ser118Phe)

Reasoning

The variant is a missense substitution, so BP4 is evaluated using REVEL only. REVEL is 0.099, meeting the generic ClinGen SVI REVEL calibration for BP4 supporting strength (<=0.29) but not the moderate threshold (<=0.183) or strong threshold (<=0.016) (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for BP4 because its splice-impact prediction cannot establish tolerance of a missense amino-acid substitution, and the BayesDel score lacks a generic ACMG-strength calibration.

Rule

Generic ACMG/ClinGen SVI REVEL calibration; BP4 is supporting at REVEL <=0.29, moderate at <=0.183, and strong at <=0.016.

Evidence considered

• The variant is missense, NP_002682.2:p.(Ser118Phe), so REVEL is the applicable computational path and SpliceAI is excluded.
• REVEL score is 0.099, meeting BP4 supporting <=0.29 but not the moderate <=0.183 or strong <=0.016 thresholds under the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
• BayesDel has no generic ACMG-strength calibration and was not used for BP4.

Sources

Reasoning

PM1 is not met on the available evidence. No applicable POLD1 VCEP or gene-specific critical-domain table is available, and the hotspot assessment found no statistically significant hotspot at POLD1 S118. Although gene-level context describes POLD1 proofreading biology, it does not establish that residue 118 lies in an approved critical functional domain sufficient for PM1.

Rule

PM1 requires a well-established critical functional domain or hotspot with no benign variation supporting that region.

Evidence considered

• The cancer-hotspot query for POLD1 S118 returned no statistically significant hotspot row.
• OncoKB provides gene-level proofreading-domain context but does not establish residue 118 as an approved critical functional domain position.

Still missing

• A governing POLD1 specification or authoritative domain map with residue boundaries is needed to assess PM1 definitively.

Sources

Reasoning

No governing POLD1-specific rule mandates a non-cancer or exome-only source, so the default all-comers gnomAD v2.1 and gnomAD v4.1 entries were used, with the non-cancer subsets as corroboration. The ClinGen SVI supporting PM2 threshold supplied for this assessment is AF <= 0.0001. The variant has gnomAD v2.1 AF 8.55377e-05 (24/280578 alleles; 0 homozygotes) and gnomAD v4.1 AF 7.87149e-05 (127/1613418 alleles; 0 homozygotes); the highest default all-comers subpopulation frequencies are 0.000696185 and 0.000433406, respectively, which exceed the threshold. Because the criterion must account for ancestry-specific frequency rather than only the aggregate total, PM2 is not securely met from the complete population evidence despite the aggregate totals being below 0.0001. The non-cancer subsets likewise have popmax frequencies above the threshold, including 0.000599880 in gnomAD v2.1 non-cancer and 0.000794913 in gnomAD v3.1 non-cancer. Therefore PM2 is not met at supporting strength when ancestry-specific frequencies are considered.

Rule

PM2 (supporting): allele frequency <= 0.0001 (ClinGen SVI supporting downgrade; Richards et al. 2015, PMID:25741868) - not securely satisfied because ancestry-specific frequencies exceed 0.0001.

Evidence considered

• Default all-comers gnomAD v2.1: total AF 8.55377e-05 (24/280578 alleles), 0 homozygotes; highest subpopulation Remaining individuals AF 0.000696185 (5/7182 alleles), 0 homozygotes.
• Default all-comers gnomAD v4.1: total AF 7.87149e-05 (127/1613418 alleles), 0 homozygotes; highest subpopulation Admixed American AF 0.000433406 (26/59990 alleles), 0 homozygotes; grpmax FAF 0.0003034.
• Non-cancer corroboration: gnomAD v2.1 non-cancer exomes total AF 7.66186e-05 with highest subpopulation AF 0.000599880; gnomAD v3.1 non-cancer genomes total AF 0.0001555 with highest subpopulation AF 0.000794913; both have 0 homozygotes.
• The supplied PM2 supporting threshold is AF <= 0.0001 under the ClinGen SVI downgrade recommendation (Richards et al. 2015, PMID:25741868).
• A ClinVar submission reports that frequency data at this position may be unreliable because of poor gnomAD data-quality metrics; the population verdict therefore warrants human review if PM2 is being considered despite the ancestry-specific frequencies.

Still missing

• A ClinVar submission notes poor data-quality metrics at this position in gnomAD, so the reported frequencies may be unreliable; this reinforces the need for human review of PM2 rather than supporting application.

Sources

Reasoning

The variant is a missense substitution, so PP3 is evaluated using REVEL only. REVEL is 0.099, which is below the generic calibrated PP3 supporting threshold of >=0.644 (and below the moderate threshold of >=0.773 and strong threshold of >=0.932) from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The SpliceAI max delta of 0.002 is not used for a missense PP3 assessment, and the BayesDel score is not applicable because no generic ACMG-strength calibration is established.

Rule

Generic ACMG/ClinGen SVI REVEL calibration; PP3 requires REVEL >=0.644 for supporting strength, >=0.773 for moderate strength, or >=0.932 for strong strength.

Evidence considered

• The variant is missense, NP_002682.2:p.(Ser118Phe), so REVEL is the applicable computational path and SpliceAI is excluded.
• REVEL score is 0.099, below PP3 supporting >=0.644, moderate >=0.773, and strong >=0.932 under the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
• BayesDel has no generic ACMG-strength calibration and was not used for PP3.

Sources

Reasoning

The exact variant is present in ClinVar, but the ClinVar record reports no expert-panel submissions and only ordinary single-submitter laboratory assertions, including uncertain-significance and likely-benign classifications. Under the required rule, PP5 is restricted to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; that qualifying assertion is absent.

Rule

PP5 may be applied only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and aggregate labels are excluded.

Evidence considered

• ClinVar exact match NM_002691.4(POLD1):c.353C>T (p.Ser118Phe), Variation ID 239345, reports expert_panel_submissions = 0.
• The exact-variant ClinVar submissions are ordinary single-submitter laboratory assertions, summarized as Uncertain significance from 9 laboratories and Likely benign from 3 laboratories; these do not qualify for PP5.
• The reviewed PMID:25394175 extract does not mention this variant and cannot supply a qualifying expert-panel assertion.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.

Sources

Reasoning

No governing POLD1 ClinGen CSPEC, VCEP specification, or local gene framework was available, so the generic ACMG/AMP BA1 threshold of allele frequency >= 0.05 (Richards et al. 2015, PMID:25741868) applies. The default all-comers population sources show gnomAD v2.1 AF 8.55377e-05 (24/280578 alleles, 0 homozygotes; highest subpopulation AF 0.000696185) and gnomAD v4.1 AF 7.87149e-05 (127/1613418 alleles, 0 homozygotes; highest subpopulation AF 0.000433406), all far below 0.05. The gnomAD v2.1 non-cancer exome AF is 7.66186e-05 and the gnomAD v3.1 non-cancer genome AF is 0.0001555, also far below BA1; therefore BA1 is not met.

Rule

BA1 (stand-alone benign): allele frequency >= 0.05 (ACMG/AMP 2015, Richards et al. 2015, PMID:25741868) - not satisfied; maximum default all-comers subpopulation AF 0.000696185.

Evidence considered

• No governing POLD1 ClinGen CSPEC, VCEP specification, or local custom gene framework was available; generic ACMG/AMP thresholds were therefore used.
• gnomAD v2.1 all-comers: AF 8.55377e-05 (24/280578 alleles), 0 homozygotes; highest subpopulation Remaining individuals AF 0.000696185 (5/7182 alleles), 0 homozygotes.
• gnomAD v4.1 all-comers: AF 7.87149e-05 (127/1613418 alleles), 0 homozygotes; highest subpopulation Admixed American AF 0.000433406 (26/59990 alleles), 0 homozygotes.
• Non-cancer corroboration: gnomAD v2.1 non-cancer exomes AF 7.66186e-05 (18/234930 alleles), 0 homozygotes; gnomAD v3.1 non-cancer genomes AF 0.0001555 (23/147910 alleles), 0 homozygotes.
• BA1 stand-alone threshold: allele frequency >= 0.05, ACMG/AMP 2015 (Richards et al. 2015, PMID:25741868).

Sources

Reasoning

No governing POLD1-specific population specification or disease prevalence/penetrance data sufficient to derive a gene-specific maximum credible allele frequency were available, so the supplied generic BS1 threshold of AF >= 0.01 was applied. The default all-comers gnomAD v2.1 frequency is 8.55377e-05, with a highest subpopulation AF of 0.000696185, and gnomAD v4.1 frequency is 7.87149e-05, with a highest subpopulation AF of 0.000433406; the non-cancer subsets are similarly rare at 7.66186e-05 in gnomAD v2.1 exomes and 0.0001555 in gnomAD v3.1 genomes. These values are well below 0.01, so BS1 is not met.

Rule

BS1 (strong benign): allele frequency >= 0.01 generic SVI default; gene-specific derivation preferred (Whiffin et al. 2017, PMID:28518168) - not satisfied; maximum default all-comers subpopulation AF 0.000696185.

Evidence considered

• No governing POLD1-specific population rule was available; the supplied generic SVI BS1 threshold of AF >= 0.01 was used, with gene-specific derivation preferred.
• gnomAD v2.1 all-comers: total AF 8.55377e-05 (24/280578 alleles); highest subpopulation AF 0.000696185 (5/7182 alleles), 0 homozygotes.
• gnomAD v4.1 all-comers: total AF 7.87149e-05 (127/1613418 alleles); highest subpopulation AF 0.000433406 (26/59990 alleles), 0 homozygotes.
• Non-cancer corroboration: gnomAD v2.1 non-cancer exomes AF 7.66186e-05 and gnomAD v3.1 non-cancer genomes AF 0.0001555, both with 0 homozygotes.
• The generic BS1 threshold of AF >= 0.01, with per-gene derivation preferred, is the supplied SVI default associated with Whiffin et al. 2017 (PMID:28518168).

Still missing

• No POLD1 disease prevalence, penetrance, or allelic-heterogeneity estimates were available to calculate a gene-specific maximum credible allele frequency; the generic 0.01 threshold was used, and the verdict remains negative because observed frequencies are much lower.

Sources

Reasoning

BS2 requires observation in a healthy adult for a disorder in which full penetrance is expected at an early age, with the relevant genotype depending on inheritance. The population data provide no per-carrier phenotype, age, or health-status annotation, so heterozygous carriers cannot be established as healthy adults; additionally, no homozygotes were observed in gnomAD v2.1 (0), gnomAD v2.1 non-cancer exomes (0), gnomAD v4.1 (0), or gnomAD v3.1 non-cancer genomes (0). The available case evidence does not establish an early-onset, fully penetrant POLD1 disorder that would make these population observations satisfy BS2, so the criterion is not met.

Rule

BS2 (strong benign): observed in a healthy adult individual for a disorder with full penetrance expected at an early age - not satisfied; no phenotyped healthy adult carriers and no homozygotes observed.

Evidence considered

• Homozygote counts are zero in gnomAD v2.1 all-comers, gnomAD v2.1 non-cancer exomes, gnomAD v4.1 all-comers, and gnomAD v3.1 non-cancer genomes.
• The observed carriers are not accompanied by individual-level phenotype, age, or health-status information, so they cannot be counted as healthy adults for BS2.
• The supplied generic BS2 definition requires observation in a healthy adult for a disorder with full penetrance expected at an early age; the available evidence does not establish that premise for this POLD1 variant or disease context.
• Generic ACMG/AMP guidance was used because no governing POLD1-specific framework was available (Richards et al. 2015, PMID:25741868).

Still missing

• gnomAD lacks individual-level phenotype, age, and health-status annotations, so unaffected adult status of heterozygous carriers cannot be verified.

Sources

Reasoning

The exact variant has ordinary ClinVar laboratory submissions with likely-benign classifications, but the record reports zero expert-panel submissions. Under the required rule, BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions and aggregate ClinVar labels cannot trigger BP6.

Rule

BP6 may be applied only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions and aggregate labels are excluded.

Evidence considered

• ClinVar exact match NM_002691.4(POLD1):c.353C>T (p.Ser118Phe), Variation ID 239345, reports expert_panel_submissions = 0.
• The exact-variant ClinVar record includes ordinary single-submitter Likely benign assertions, but these are explicitly excluded from BP6 by the governing instruction.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign classification is present.

Sources

Reasoning

PS1 requires a different nucleotide change producing the same amino-acid substitution to be established as pathogenic. The available ClinVar record for NM_002691.4:c.353C>T (p.Ser118Phe) is conflicting and has no expert-panel submission, while the reviewed literature contains no POLD1 p.Ser118 substitution or validated pathogenic same-amino-acid comparator. A pathogenic same-amino-acid comparator therefore could not be confirmed.

Rule

PS1 requires a different nucleotide change producing the same amino-acid change as an established pathogenic variant.

Evidence considered

• ClinVar lists this variant as conflicting/uncertain, with both uncertain-significance and likely-benign submissions and no expert-panel submission.
• The reviewed paper extracts contain no POLD1 p.Ser118 substitution or variant-specific pathogenicity evidence.

Still missing

• Confirm whether any independently established pathogenic POLD1 variant produces p.Ser118Phe or the same amino-acid change by another nucleotide substitution.

Sources

Reasoning

No case-specific evidence documents a confirmed de novo occurrence of NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)) in an affected proband, including verified parental testing that excludes the variant in both biological parents. The available case materials do not provide a parent-child trio result, parental genotypes, maternity/paternity confirmation, or phenotype documentation sufficient to assess PS2.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity/paternity confirmed; stronger application requires confirmed parental absence and appropriate phenotype.

Evidence considered

• The case-specific materials identify NM_002691.4:c.353C>T as a POLD1 missense variant but provide no documented proband-parent trio results or confirmed de novo observation.
• No relevant fetched publication contains variant-specific de novo or parental-testing evidence; the available extracted publications do not mention this variant.

Still missing

• Affected proband phenotype and clinical diagnosis are not documented.
• Parental genotypes and test methods are not documented.
• Biological parentage and whether the variant is confirmed de novo are not documented.

Reasoning

No applicable POLD1-specific VCEP specification was identified, so generic ACMG/AMP functional-evidence guidance applies. The available case evidence contains no variant-specific, validated functional assay for NM_002691.4:c.353C>T (NP_002682.2:p.Ser118Phe), and no assay controls, biological readout, or calibrated functional effect is reported. Predictive scores, ClinVar classifications, COSMIC occurrence, and general guideline papers do not establish PS3. Therefore PS3 cannot be assessed.

Evidence considered

• The governing-materials review found no applicable POLD1-specific VCEP specification.
• The available variant-specific evidence does not contain a validated cellular, biochemical, or other biologically relevant assay for NM_002691.4:c.353C>T (NP_002682.2:p.Ser118Phe).
• General ACMG/AMP guidance states that functional studies may inform missense interpretation, but it does not provide variant-specific functional evidence for this variant.

Still missing

• A variant-specific functional study with appropriate positive and negative controls is needed.
• The study should measure a biologically relevant POLD1 function and report quantitative results sufficient for strength calibration.

Sources

Reasoning

No variant-specific case-control enrichment, statistically supported excess of affected carriers, odds ratio, likelihood ratio, or comparable prevalence analysis was identified. The available ClinVar records are ordinary single-submitter laboratory assertions and do not provide PS4 case-control evidence. No applicable POLD1 VCEP framework was available, so generic ACMG/AMP PS4 concepts apply, but the required affected-versus-control data are absent.

Rule

Generic ACMG/AMP PS4: statistically significant increased prevalence of the variant in affected individuals compared with controls; no usable case-control evidence is present.

Evidence considered

• No applicable POLD1 ClinGen CSPEC/VCEP specification was retrieved; generic ACMG/AMP criteria therefore govern.
• The case materials contain no variant-specific case-control cohort, enrichment statistic, odds ratio, likelihood ratio, or prevalence comparison for NM_002691.4:c.353C>T (p.Ser118Phe).

Still missing

• Variant-specific affected-case and control counts or a validated case-control enrichment statistic are unavailable.

Sources

Reasoning

No affected-proband observation, biallelic genotype, pathogenic/likely pathogenic allele in trans, phase result, or inheritance information is documented for NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)). Therefore the recessive allelic evidence required for PM3 cannot be assessed.

Rule

PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive disorder; phase and relevant inheritance evidence must be established.

Evidence considered

• The available case evidence identifies the variant as NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)) but contains no affected-proband, biallelic, phase, or parental-inheritance observation relevant to PM3.
• No applicable POLD1-specific VCEP or gene-specific framework was available; generic PM3 logic therefore requires documented recessive occurrence with a pathogenic or likely pathogenic allele in trans, which is absent here.

Still missing

• Affected-proband genotype and phenotype data are unavailable.
• No second pathogenic or likely pathogenic POLD1 variant is documented.
• Phase (trans versus cis) is not established.
• Inheritance and parental testing information are unavailable.

Reasoning

PM5 requires a different missense change at the same residue that is established as pathogenic. The case-specific comparator search reported no same-residue candidates and could not safely confirm classic PM5 semantics; no reviewed paper supplied a validated pathogenic POLD1 variant at Ser118.

Rule

PM5 requires a novel missense change at a residue where another missense change is established as pathogenic.

Evidence considered

• The case-specific PM5 candidate record contains zero same-residue candidates and explicitly does not support automatic PM5 application.
• The reviewed paper extracts contain no POLD1 residue-118 pathogenic comparator.

Still missing

• Review ClinVar and primary literature for independently established pathogenic POLD1 missense variants at residue 118.

Reasoning

No case-specific evidence documents a suspected de novo occurrence of NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)) in an affected proband. There are no reported parental genotypes, parentage information, or clinical details establishing a compatible phenotype, so PM6 cannot be applied even at supporting strength.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease but without confirmation of maternity/paternity; the phenotype should be compatible and the evidence should be case-specific.

Evidence considered

• The available case materials contain no variant-specific report of a suspected de novo POLD1 c.353C>T occurrence.
• No relevant fetched publication contains variant-specific parental, de novo, or phenotype evidence; the available extracted publications do not mention this variant.

Still missing

• Affected proband phenotype and clinical diagnosis are not documented.
• Parental testing or reliable parentage information is not documented.
• The variant's de novo status is not described in a case report or clinical record.

Reasoning

No familial observations are provided for NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)). The available materials contain no affected relatives, unaffected relatives, informative meioses, genotype-phenotype relationships, or segregation counts from which supporting, moderate, or strong PP1 evidence could be assigned.

Rule

Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses and the quality of phenotype and genotype data.

Evidence considered

• The case-specific evidence contains no documented family segregation data for the POLD1 c.353C>T variant.
• No relevant fetched publication provides variant-specific segregation or familial genotype-phenotype evidence; the available extracted publications do not mention this variant.

Still missing

• Family pedigree and affected-relative phenotypes are not documented.
• Genotypes of informative relatives are not documented.
• Informative meioses and segregation counts are not documented.

Reasoning

PP2 requires a missense mechanism to be established for the gene together with a low rate of benign missense variation. The available materials describe POLD1 proofreading biology but provide no applicable gene-specific PP2 rule, validated benign-missense-rate analysis, or sufficiently specific evidence to apply PP2 to p.Ser118Phe.

Rule

PP2 requires a missense mechanism that is a common cause of disease in the gene and a low rate of benign missense variation.

Evidence considered

• OncoKB describes POLD1 proofreading biology and disease-associated exonuclease-domain context, but it does not provide a PP2 rule or benign-missense-rate calibration.

Still missing

• Obtain a validated POLD1-specific PP2 framework or quantitative benign-missense constraint analysis.

Sources

Reasoning

No individual-level phenotype, clinical diagnosis, or phenotype-specific disease presentation for the carrier of NM_002691.4:c.353C>T was supplied. The available literature extracts do not mention this variant or provide a phenotype for its carrier. Therefore, highly specific phenotype matching to a POLD1-related disorder cannot be assessed.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; no carrier phenotype is available.

Evidence considered

• The case materials do not provide individual-level clinical features, a confirmed diagnosis, or a phenotype summary for the variant carrier.
• The reviewed literature extract for PMID:25394175 does not mention POLD1, c.353C>T, or p.Ser118Phe and provides no variant-specific clinical phenotype.

Still missing

• Carrier-level phenotype and confirmed clinical diagnosis are unavailable.
• A disease-specific phenotype definition applicable to this case is unavailable.

Sources

Reasoning

No applicable POLD1-specific VCEP specification was identified, so generic ACMG/AMP functional-evidence guidance applies. The available case evidence contains no variant-specific, validated functional assay demonstrating preserved POLD1 function, and no assay controls, biological relevance assessment, or quantitative benign-effect calibration is reported. Predictive scores, ClinVar classifications, COSMIC occurrence, and general guideline papers cannot establish BS3. Therefore BS3 cannot be assessed.

Evidence considered

• The governing-materials review found no applicable POLD1-specific VCEP specification.
• The available variant-specific evidence does not contain a validated cellular, biochemical, or other biologically relevant assay demonstrating preserved function for NM_002691.4:c.353C>T (NP_002682.2:p.Ser118Phe).
• General ACMG/AMP guidance states that functional studies may inform missense interpretation, but it does not provide variant-specific functional evidence for this variant.

Still missing

• A variant-specific functional study with appropriate positive and negative controls is needed.
• The study should demonstrate preserved biologically relevant POLD1 function and report quantitative results sufficient for strength calibration.

Sources

Reasoning

No familial testing data are available to show that NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)) fails to segregate with disease. The record does not identify unaffected relatives tested for the variant, their phenotypes, or the number and informativeness of non-segregating observations; therefore BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires reliable phenotype assignment and informative testing, not merely absence of reported family history.

Evidence considered

• The available case materials contain no variant-specific evidence of non-segregation in unaffected relatives.
• No relevant fetched publication provides variant-specific non-segregation or family-testing evidence; the available extracted publications do not mention this variant.

Still missing

• Unaffected relatives and their clinical phenotypes are not documented.
• Relative genotypes are not documented.
• The number and informativeness of non-segregating observations are not documented.

Reasoning

BP1 requires a gene in which truncating variants are the predominant established disease mechanism and the evaluated variant is missense. The variant is missense, but the available materials do not provide a sufficiently specific POLD1 disease-variant spectrum or governing specification showing that truncating variants predominate over other pathogenic mechanisms; BP1 therefore cannot be applied.

Rule

BP1 applies to a missense variant in a gene for which disease is known to be caused predominantly by truncating variants.

Evidence considered

• The case normalization identifies NM_002691.4:c.353C>T as the missense variant p.Ser118Phe.
• No applicable gene-specific framework establishes truncating variants as the predominant POLD1 disease mechanism.

Still missing

• Confirm the established POLD1 pathogenic variant spectrum and whether truncating variants predominate for the relevant disease context.

Reasoning

No individual-level observation documents NM_002691.4:c.353C>T (NP_002682.2:p.(Ser118Phe)) occurring with another pathogenic or likely pathogenic variant in cis or trans, and no phase or phenotype context is available. Therefore BP2 cannot be assessed.

Rule

BP2 requires documented occurrence of the variant with another pathogenic or likely pathogenic variant in cis or trans, with sufficient individual-level and phase context to support benign co-occurrence evidence.

Evidence considered

• The available case evidence contains no individual-level co-occurrence record for this variant with another pathogenic or likely pathogenic variant.
• Phase, inheritance, and affected/unaffected status are not documented, so the BP2 co-occurrence observation cannot be evaluated.

Still missing

• No co-occurring pathogenic or likely pathogenic variant is documented.
• No cis/trans phase information is available.
• No affected or unaffected individual-level context is provided for evaluating co-occurrence.

Reasoning

No evidence was supplied that an alternative molecular basis explains the patient's phenotype, and no qualifying BP5-specific VCEP rule was available. The variant's presence in COSMIC is somatic occurrence information, not evidence that another molecular cause explains a germline phenotype, so it cannot establish BP5.

Rule

Generic ACMG/AMP BP5 concept: an alternate molecular basis explains the phenotype; no such evidence is available in this case.

Evidence considered

• The case materials do not document an alternative pathogenic variant or molecular diagnosis explaining a patient's phenotype.
• COSMIC reports two somatic occurrences of the variant, but somatic occurrence alone does not establish BP5 for germline phenotype interpretation.

Still missing

• A documented alternative molecular basis for the phenotype is unavailable.
• A relevant phenotype and testing context for evaluating coexisting molecular causes are unavailable.