MUTYH c.505G>A, p.(Glu169Lys)

Reasoning

The governing InSiGHT MUTYH specification is present but contains no usable population-frequency rule payload, so the supplied generic PM2 threshold is used. The variant is observed only once in gnomAD v4.1, with total AF 6.194911747287248e-07 (1/1614228 alleles), zero homozygotes, and highest subpopulation AF 1.5997440409534473e-05; it is absent from gnomAD v2.1. The total AF and every reported nonzero population frequency are below the supplied generic PM2 supporting threshold of 0.0001, so PM2 is met at supporting strength. The non-cancer subsets are also reported absent, but no governing rule requires substituting them for the default all-comers population source.

Rule

Generic PM2: supporting when allele frequency <=0.0001; default all-comers gnomAD is used because no governing VCEP population-source rule was specified.

Evidence considered

• The InSiGHT MUTYH specification is available, but its supplied ruleset has no criterion-specific population threshold; the supplied generic PM2 default was used.
• gnomAD v4.1 reports total AF 6.194911747287248e-07 from 1 alternate allele among 1,614,228 alleles, zero homozygotes, and highest subpopulation AF 1.5997440409534473e-05.
• The variant is absent from gnomAD v2.1 and from the reported non-cancer gnomAD v2.1 and v3.1 subsets.
• The supplied generic PM2 supporting threshold is AF <=0.0001, from the ClinGen SVI recommendation to downgrade PM2 to supporting (PMID:25741868).

Sources

Reasoning

NM_001128425.2:c.505G>A is a missense variant causing p.(Glu169Lys), so PP3 is evaluated through the missense REVEL path only. The REVEL score is 0.846, which meets the published ClinGen SVI REVEL calibration threshold for moderate PP3 (>=0.773; Pejaver et al. 2022, PMID:36413997). The unavailable SpliceAI result is not used because splice prediction is not the applicable path for this missense variant, and the MUTYH VCEP record contains no criterion-specific PP3 rule to override the generic calibration.

Evidence considered

• Variant normalization identifies NM_001128425.2:c.505G>A as the missense substitution NP_001121897.1:p.(Glu169Lys).
• The local REVEL lookup reports a score of 0.846 for this variant.
• The published ClinGen SVI REVEL calibration assigns moderate PP3 at REVEL >=0.773 (Pejaver et al. 2022, PMID:36413997).
• The MUTYH InSiGHT specification is present, but its supplied ruleset has no criterion-specific PP3 rule payload.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar identifies the exact variant as Uncertain significance with two clinical-laboratory submissions and no expert-panel submissions; therefore the required expert-panel pathogenic classification is absent. Ordinary laboratory submissions and the aggregate ClinVar label cannot trigger PP5.

Rule

PP5: met only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic; ordinary laboratory, aggregate, and non-expert assertions do not qualify.

Evidence considered

• The exact-variant ClinVar record reports Uncertain significance, criteria provided, single submitter, with two clinical-laboratory submissions.
• The ClinVar submission audit reports 0 expert-panel submissions and 0 usable criterion-lead submissions; the ordinary laboratory assertions are excluded from PP5.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but contains no usable population-frequency rule payload, so the supplied generic ACMG/AMP BA1 threshold is used. In gnomAD v4.1, the variant has total allele frequency 6.194911747287248e-07 (1/1614228 alleles), with the highest reported subpopulation frequency 1.5997440409534473e-05 (1/62510 alleles), both far below the stand-alone BA1 threshold of 0.05 from ACMG/AMP 2015 (PMID:25741868). The variant is absent from gnomAD v2.1 and has zero observed homozygotes in gnomAD v4.1; therefore BA1 is not met.

Rule

Generic BA1: stand-alone when allele frequency >=0.05; governing MUTYH specification had no usable population rule payload.

Evidence considered

• The InSiGHT MUTYH specification is available, but its supplied ruleset has no criterion-specific population threshold; generic ACMG/AMP defaults were therefore applied.
• gnomAD v4.1 reports 1 alternate allele among 1,614,228 total alleles (AF 6.194911747287248e-07); the highest observed subpopulation AF is 1.5997440409534473e-05 in Remaining individuals.
• The generic BA1 stand-alone threshold is AF >=0.05, specified here from ACMG/AMP 2015 (PMID:25741868).

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but contains no usable population-frequency rule payload, so the supplied generic BS1 threshold is used. gnomAD v4.1 reports a total allele frequency of 6.194911747287248e-07 (1/1614228 alleles), and its highest reported subpopulation frequency is 1.5997440409534473e-05 (1/62510 alleles), both below the generic BS1 threshold of 0.01. The variant is absent from gnomAD v2.1, so the available population data do not support a frequency higher than expected for disease and BS1 is not met.

Rule

Generic BS1: strong benign evidence when allele frequency >=0.01; governing MUTYH specification had no usable population rule payload.

Evidence considered

• The InSiGHT MUTYH specification is available, but its supplied ruleset has no criterion-specific population threshold; the supplied generic BS1 default was used.
• gnomAD v4.1 reports total AF 6.194911747287248e-07 and highest observed subpopulation AF 1.5997440409534473e-05.
• The supplied generic BS1 threshold is AF >=0.01; per-gene derivation is preferred, but no MUTYH-specific threshold was available in the governing specification.

Sources

Reasoning

BS2 requires observation in healthy adults in a manner inconsistent with the disease mechanism. MUTYH-associated polyposis is autosomal recessive, and gnomAD v4.1 reports zero homozygotes for this variant; the single observed allele is heterozygous and does not establish an unaffected biallelic individual. No variant-specific healthy-adult or penetrance observation is supplied. Therefore BS2 is not met.

Rule

BS2 requires healthy-adult observation inconsistent with the disease mechanism; for an autosomal-recessive disorder, a heterozygous carrier observation alone does not satisfy BS2.

Evidence considered

• The governing MUTYH framework identifies familial adenomatous polyposis 2 as autosomal recessive.
• gnomAD v4.1 reports total AC 1 and homozygotes 0; the highest-frequency subpopulation also has homozygotes 0.
• A single heterozygous population observation cannot establish BS2 for an autosomal-recessive condition, and no variant-specific healthy-adult or penetrance data are available.

Sources

Reasoning

NM_001128425.2:c.505G>A is a missense variant, so BP4 is evaluated through the missense REVEL path only. The REVEL score is 0.846, which does not meet any published benign REVEL BP4 threshold; the most permissive supporting threshold is <=0.29 (Pejaver et al. 2022, PMID:36413997). The unavailable SpliceAI result cannot provide BP4 evidence for this missense variant, and the MUTYH VCEP record contains no criterion-specific BP4 rule to override the generic calibration.

Evidence considered

• Variant normalization identifies NM_001128425.2:c.505G>A as the missense substitution NP_001121897.1:p.(Glu169Lys).
• The local REVEL lookup reports a score of 0.846 for this variant.
• The published ClinGen SVI REVEL calibration requires REVEL <=0.29 even for supporting BP4 (Pejaver et al. 2022, PMID:36413997).
• The MUTYH InSiGHT specification is present, but its supplied ruleset has no criterion-specific BP4 rule payload.

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar identifies the exact variant as Uncertain significance with two clinical-laboratory submissions and no expert-panel submissions; therefore the required expert-panel benign classification is absent. Ordinary laboratory submissions and the aggregate ClinVar label cannot trigger BP6.

Rule

BP6: met only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign; ordinary laboratory, aggregate, and non-expert assertions do not qualify.

Evidence considered

• The exact-variant ClinVar record reports Uncertain significance, criteria provided, single submitter, with two clinical-laboratory submissions.
• The ClinVar submission audit reports 0 expert-panel submissions; no exact-variant expert-panel Benign or Likely benign assertion exists to support BP6.

Sources

Reasoning

PS1 cannot be assessed because the available evidence does not identify a previously established pathogenic or likely pathogenic variant producing the same amino-acid change p.Glu169Lys. ClinVar classifies the target variant as uncertain significance, and the retrieved literature contains no variant-specific or same-amino-acid evidence. The MUTYH VCEP framework is present but its rule payload is empty and provides no PS1 rule or comparator evidence.

Evidence considered

• The target variant is reported in ClinVar as uncertain significance from two clinical laboratories; this does not establish PS1.
• The retrieved paper extracts contain no mention of MUTYH c.505G>A or p.Glu169Lys and provide no same-amino-acid comparator.
• The InSiGHT MUTYH framework is identified, but its rule payload is empty and supplies no applicable PS1 rule.

Still missing

• A validated pathogenic or likely pathogenic MUTYH variant causing p.Glu169Lys is not available.
• A curated same-amino-acid comparator search is needed if such evidence exists outside the supplied sources.

Sources

Reasoning

The variant is missense MUTYH c.505G>A (p.Glu169Lys), but the available case evidence contains no documented proband phenotype, parental genotypes, maternity/paternity confirmation, or validated de novo observation. Therefore, PS2 cannot be assessed.

Evidence considered

• The governing InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive, but the retrieved specification provides no criterion-specific PS2 rule and no case-level parental or de novo data are available.
• The case materials identify NM_001128425.2:c.505G>A as a missense variant encoding p.(Glu169Lys), without reporting parental testing or a confirmed de novo event.

Still missing

• Documented proband phenotype consistent with the relevant MUTYH-associated condition
• Parental testing results for c.505G>A
• Confirmation of maternity and paternity
• Evidence that the variant is absent from both tested parents

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but contains no criterion-specific functional rules. The supplied case evidence identifies the variant as NM_001128425.2:c.505G>A (p.Glu169Lys), but provides no validated functional assay, assay controls, biological readout, or variant-specific experimental result demonstrating a damaging effect. The reviewed literature extracts contain no mention of this variant and no functional assay evidence applicable to it. Therefore PS3 cannot be assessed.

Evidence considered

• The InSiGHT MUTYH Version 1.0 specification is the governing framework, but its supplied ruleset has an empty criterion list and no PS3 functional calibration.
• The case evidence identifies NM_001128425.2:c.505G>A as the missense variant p.Glu169Lys.
• The extracted literature available for this case does not mention c.505G>A or p.Glu169Lys and provides no variant-specific functional assay, controls, or biological readout.

Still missing

• A validated functional assay for NM_001128425.2:c.505G>A (p.Glu169Lys) with appropriate positive and negative controls is needed.
• The assay must measure a biologically relevant MUTYH function and provide a quantitative or otherwise interpretable variant-specific result.

Sources

Reasoning

PS4 requires a statistically significant excess of affected individuals carrying the exact variant relative to appropriate controls, or other qualifying case-control enrichment. The available evidence contains no exact-variant case series, case-control counts, odds ratio, relative risk, p-value, or other validated enrichment metric for NM_001128425.2:c.505G>A (p.Glu169Lys). Gene-level descriptions of MUTYH-associated polyposis do not establish variant-specific enrichment.

Rule

Generic PS4: apply only when affected individuals with the exact variant are significantly enriched compared with appropriate controls; no qualifying exact-variant enrichment data are available.

Evidence considered

• The MUTYH InSiGHT specification is present but contains no extracted PS4 rule or usable criterion-specific threshold.
• The reviewed colorectal cancer guidance papers describe MUTYH-associated polyposis at the gene-disease level but do not report this exact variant or variant-specific enrichment data.

Still missing

• Exact-variant affected-case and control counts or a validated case-control enrichment statistic are unavailable.

Sources

Reasoning

PM1 cannot be assessed because vcep_materials.json contains no MUTYH domain_tables entry, and the supplied evidence does not establish that residue 169 lies in a validated critical functional domain or hotspot. The hotspot query returned no statistically significant hotspot for MUTYH E169. The MUTYH VCEP framework is present but incomplete for this purpose, with an empty rule payload.

Evidence considered

• vcep_materials.json has an empty domain_tables object, so there is no authoritative approved domain entry to check for residue 169.
• The cancer-hotspot query for MUTYH E169 found no statistically significant hotspot.
• The MUTYH VCEP framework has an empty rule payload and does not provide a PM1 region rule.

Still missing

• An authoritative MUTYH critical-domain table or validated functional-region annotation covering residue 169 is unavailable.
• The incomplete VCEP framework does not define an applicable PM1 rule.

Sources

Reasoning

The applicable InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive, so PM3 would require this c.505G>A variant in an affected individual with a second pathogenic or likely pathogenic MUTYH variant demonstrated in trans, or equivalent validated biallelic evidence. The available case evidence documents no affected-proband observation, second MUTYH variant, phase, compound-heterozygous state, or homozygous state for this variant. Therefore PM3 cannot be assigned.

Evidence considered

• The governing InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive.
• No affected-proband observation, second pathogenic or likely pathogenic MUTYH variant, homozygous/compound-heterozygous genotype, or cis/trans phase is present in the available case evidence.
• The variant is NM_001128425.2:c.505G>A (NP_001121897.1:p.(Glu169Lys)); the available ClinVar submissions are uncertain significance and provide no validated allelic-phase evidence.

Still missing

• Affected-proband clinical observation linked to NM_001128425.2:c.505G>A is not documented.
• A second pathogenic or likely pathogenic MUTYH variant is not documented.
• Cis/trans phase or validated biallelic genotype is not documented.

Sources

Reasoning

PM5 cannot be assessed because no alternate missense variant at MUTYH residue 169 with a validated pathogenic or likely pathogenic classification is provided. The collected PM5 candidate summary reports zero same-residue candidates, while the target's ClinVar record is uncertain significance and cannot serve as a pathogenic comparator. The VCEP rule payload is empty.

Evidence considered

• The PM5 candidate summary reports zero same-residue candidates and does not establish classic PM5 semantics for this case.
• ClinVar classifies the target variant as uncertain significance, so it cannot be used as evidence of a pathogenic alternate substitution.
• The MUTYH VCEP rule payload is empty and supplies no alternate-residue PM5 rule.

Still missing

• A curated search for pathogenic or likely pathogenic alternate substitutions at residue 169 is needed.
• The available PM5 candidate collection contains zero same-residue candidates.

Sources

Reasoning

No publication or case record in the supplied evidence documents MUTYH c.505G>A (p.Glu169Lys) as a presumed de novo variant without parental testing. The available literature extracts do not report this variant or a relevant family observation. Therefore, PM6 cannot be assessed.

Evidence considered

• The supplied paper extracts for the fetched publications do not mention MUTYH c.505G>A or p.(Glu169Lys), and none reports a presumed de novo observation for this variant.
• No case-level presumed de novo observation, parental-testing status, or phenotype description is present in the supplied evidence.

Still missing

• A variant-specific publication or clinical report describing the proband
• Evidence that parental testing was unavailable or not performed
• Phenotype consistency supporting a de novo interpretation

Reasoning

The MUTYH specification establishes an autosomal-recessive disease context, but the case evidence provides no affected relatives, unaffected relatives, parental phase, biallelic genotypes, or informative meioses. No segregation observations are therefore available to support or refute PP1.

Evidence considered

• The governing InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive, but it supplies no case-specific segregation observations for c.505G>A.
• The case evidence contains no family pedigree, affected-relative testing, unaffected-relative testing, phase information, or meiosis count for NM_001128425.2:c.505G>A.

Still missing

• Pedigree and phenotype information for relatives
• Genotypes of affected and unaffected relatives
• Phasing of the proband's alleles and identification of a second MUTYH variant if relevant
• Number of informative meioses and segregation observations

Sources

Reasoning

PP2 cannot be assessed because the supplied evidence does not provide a validated gene-level estimate showing that pathogenic missense variation is a common mechanism for MUTYH-related disease. The available MUTYH framework is incomplete and contains no PP2 rule or quantitative missense mechanism assessment. Gene-level statements that MUTYH is a DNA glycosylase do not establish the required missense enrichment.

Evidence considered

• The MUTYH VCEP framework has an empty rule payload and provides no PP2 specification.
• OncoKB supplies only non-variant-specific gene context and does not quantify the proportion or mechanism of pathogenic MUTYH missense variants.

Still missing

• A gene-level analysis or governing VCEP rule quantifying pathogenic missense enrichment for MUTYH is unavailable.

Sources

Reasoning

PP4 requires the patient's phenotype or family history to be highly specific for a disease associated with the gene. The evidence supplied for this variant contains no patient phenotype, polyp burden, cancer history, family history, or other clinical presentation. General descriptions of MUTYH-associated polyposis and referral thresholds cannot substitute for phenotype information from this case.

Rule

Generic PP4: apply only when the patient's phenotype or family history is highly specific for a disease associated with the gene; patient-level phenotype evidence is absent.

Evidence considered

• A reviewed referral guideline identifies colorectal cancer with at least 10 cumulative adenomatous colon polyps as a context for considering MUTYH-associated polyposis, but it provides no phenotype for this patient.
• A reviewed hereditary colorectal cancer guideline describes MAP as multiple colorectal polyps with autosomal-recessive inheritance, but does not document this patient's clinical presentation.

Still missing

• Patient-level phenotype and family-history information are unavailable.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but contains no criterion-specific functional rules. The supplied case evidence identifies the variant as NM_001128425.2:c.505G>A (p.Glu169Lys), but provides no validated functional assay, assay controls, biological readout, or variant-specific experimental result demonstrating a normal or benign effect. The reviewed literature extracts contain no mention of this variant and no functional assay evidence applicable to it. Therefore BS3 cannot be assessed.

Evidence considered

• The InSiGHT MUTYH Version 1.0 specification is the governing framework, but its supplied ruleset has an empty criterion list and no BS3 functional calibration.
• The case evidence identifies NM_001128425.2:c.505G>A as the missense variant p.Glu169Lys.
• The extracted literature available for this case does not mention c.505G>A or p.Glu169Lys and provides no variant-specific functional assay, controls, or biological readout.

Still missing

• A validated functional assay for NM_001128425.2:c.505G>A (p.Glu169Lys) with appropriate positive and negative controls is needed.
• The assay must measure a biologically relevant MUTYH function and provide a quantitative or otherwise interpretable variant-specific result.

Sources

Reasoning

The case evidence does not identify affected or unaffected relatives who were tested for MUTYH c.505G>A, nor does it provide phenotype assessments or informative family structure. Non-segregation cannot be evaluated, so BS4 is not assessed.

Evidence considered

• No affected or unaffected relatives tested for c.505G>A are documented in the supplied evidence.
• No family-based phenotype-genotype comparison is available to demonstrate that the variant fails to segregate with disease.

Still missing

• Tested affected relatives with reliable phenotype classification
• Tested unaffected relatives with reliable phenotype classification
• Family structure and age-related penetrance information
• Variant results for each informative relative

Reasoning

BP1 cannot be assessed because the supplied evidence does not establish that MUTYH-related disease is caused predominantly by truncating or other non-missense variants, nor does the MUTYH VCEP framework provide an applicable BP1 rule. The available gene-level sources do not provide a validated variant-spectrum proportion or mechanism analysis sufficient to support BP1.

Evidence considered

• The MUTYH VCEP framework has an empty rule payload and provides no BP1 specification.
• OncoKB provides general gene context but no quantitative evidence that MUTYH disease is predominantly caused by truncating variants.

Still missing

• A validated MUTYH variant-spectrum analysis or governing VCEP BP1 rule is unavailable.

Sources

Reasoning

BP2 requires a documented, interpretable allelic relationship between the variant and another pathogenic variant, such as validated cis phase or an appropriate trans observation under the applicable disease model. No second pathogenic or likely pathogenic variant, affected or unaffected carrier context, or cis/trans phase is documented for NM_001128425.2:c.505G>A. The available evidence therefore cannot establish BP2.

Evidence considered

• The governing MUTYH framework specifies an autosomal-recessive disease context but supplies no criterion-specific BP2 rule payload.
• No validated cis or trans relationship with another pathogenic or likely pathogenic variant is documented in the available case evidence.
• ClinVar contains two single-submitter uncertain-significance submissions for the variant and no phase-resolved allelic observation.

Still missing

• No second pathogenic or likely pathogenic variant is documented for the same individual.
• No validated cis/trans phase is documented.
• No phenotype and inheritance context is documented to interpret an allelic observation under BP2.

Sources

Reasoning

BP5 requires a well-established alternate molecular explanation for the patient's phenotype that reduces the likelihood that this variant is causative. No patient phenotype, alternate pathogenic molecular diagnosis, or qualifying BP5-specific evidence is provided. The absence of a qualifying alternative diagnosis is an evidence gap, not benign evidence for this variant.

Rule

BP5: apply only when an established alternate molecular diagnosis explains the phenotype and makes this variant unlikely to be causal; no qualifying evidence is available.

Evidence considered

• No qualifying alternate molecular diagnosis or BP5-specific likelihood-ratio evidence is documented for this case.

Still missing

• Patient phenotype and any confirmed alternate molecular diagnosis are unavailable.