MUTYH c.309G>A, p.(Trp103Ter)

Reasoning

PVS1 is met at full strength under the generic ClinGen SVI PVS1 framework. The variant is a nonsense substitution, NM_001128425.2:c.309G>A, producing NP_001121897.1:p.(Trp103Ter) in the ClinGen/InSiGHT-preferred MUTYH transcript. The predicted product is only 103 amino acids compared with the 550-amino-acid reference protein, placing the truncation early rather than near the C-terminus and making a functional null consequence expected through nonsense-mediated decay. The available evidence identifies no specific rule indicating NMD escape, a non-critical distal exon, a biologically irrelevant transcript, repeat-region context, or enrichment for loss-of-function variation that would require downgrading. The MUTYH gene-level loss-of-function mechanism is supported, and no MUTYH-specific PVS1 downgrade rule was identified in the governing framework; therefore, no downgrade from very strong is applied.

Rule

Generic ClinGen SVI PVS1 framework (PMC6185798); no applicable MUTYH-specific PVS1 downgrade rule identified.

Evidence considered

• The governing MUTYH framework names NM_001128425.2 as the preferred transcript and provides no gene-specific PVS1 rule payload or downgrade decision tree.
• The normalized consequence is nonsense: NM_001128425.2:c.309G>A causes NP_001121897.1:p.(Trp103Ter), with the predicted product ending at residue 103 while the reference protein ends at residue 550.
• The generic ClinGen SVI PVS1 framework supports full-strength assessment of a nonsense variant when loss of function is an established disease mechanism, with downgrades considered for NMD escape, non-critical distal regions, irrelevant exons/transcripts, or population-enriched loss-of-function regions.
• The gene-level assessment marks MUTYH loss of function as an eligible disease mechanism, and the case contains no evidence that this early truncation escapes NMD or affects only a non-critical distal region.

Still missing

• The case annotation does not provide an explicit exon number or direct RNA/NMD assay for this variant; however, the early truncation and absence of a documented escape or non-critical-region rule do not trigger a downgrade.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but does not provide a usable population-specific PM2 threshold or source override, so the supplied generic SVI PM2 threshold applies. The variant is rare in the default all-comers population datasets: gnomAD v4.1 overall AF 2.7879279004672568e-05 and maximum named-subpopulation AF 3.813404200507098e-05, with 0 homozygotes; gnomAD v2.1 overall AF 3.9763328667769435e-06, also with 0 homozygotes. These frequencies are below the supplied PM2 threshold of 0.0001, supporting PM2 at supporting strength. The non-cancer subsets are concordant (gnomAD v2.1 AF 4.220264019717074e-06; gnomAD v3.1 AF 6.758857482731119e-06).

Rule

Generic SVI PM2 supporting threshold: allele frequency <= 0.0001; no applicable MUTYH-specific override was available.

Evidence considered

• The InSiGHT MUTYH Version 1.0 framework was checked first; its retrieved rule payload contains no population-specific PM2 threshold or population-source override, so the default all-comers datasets were used.
• gnomAD v4.1 reports overall AF 2.7879279004672568e-05 from 45/1614102 alleles, maximum named-subpopulation AF 3.813404200507098e-05 in European (non-Finnish) individuals, and 0 homozygotes.
• gnomAD v2.1 reports AF 3.9763328667769435e-06 from 1/251488 alleles and 0 homozygotes; the highest named-subpopulation AF is 8.790126929432861e-06.
• The supplied generic SVI PM2 threshold is AF <= 0.0001, downgraded to supporting strength (ClinGen SVI 2020; PMID:25741868).
• Supplemental non-cancer datasets are concordant: gnomAD v2.1 non-cancer exomes AF 4.220264019717074e-06 and gnomAD v3.1 non-cancer genomes AF 6.758857482731119e-06, both with 0 homozygotes.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact-match ClinVar audit reports 14 submissions, including 12 clinical-laboratory Pathogenic assertions and one Likely pathogenic assertion, but zero expert-panel submissions; its review status is criteria provided, multiple submitters, no conflicts rather than expert-panel review. Ordinary laboratory submissions and aggregate ClinVar labels do not trigger PP5.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• The exact-match ClinVar audit identifies the variant record as NM_001048174.2(MUTYH):c.225G>A (p.Trp75Ter), equivalent to the case variant, and reports expert_panel_submissions = 0.
• ClinVar reports Pathogenic and Likely pathogenic laboratory submissions, but no expert-panel classification; these assertions are expressly excluded from PP5 under the governing instruction.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but does not provide a usable population-specific threshold or source override, so the supplied generic ACMG/AMP BA1 threshold applies. The highest observed all-comers gnomAD v4.1 population frequency is 3.813404200507098e-05 in European (non-Finnish) individuals, with overall frequency 2.7879279004672568e-05 and 0 homozygotes; this is far below the stand-alone BA1 threshold of 0.05 from ACMG/AMP 2015 (PMID:25741868). The supplemental non-cancer values are also below BA1 (gnomAD v2.1 non-cancer exomes AF 4.220264019717074e-06; gnomAD v3.1 non-cancer genomes AF 6.758857482731119e-06).

Rule

Generic ACMG/AMP BA1 stand-alone threshold: allele frequency >= 0.05; no applicable MUTYH-specific override was available.

Evidence considered

• The InSiGHT MUTYH Version 1.0 framework was checked first; its retrieved rule payload contains no population-specific BA1 threshold or population-source override.
• gnomAD v4.1 reports overall AF 2.7879279004672568e-05 from 45/1614102 alleles, maximum named-subpopulation AF 3.813404200507098e-05 in European (non-Finnish) individuals, and 0 homozygotes.
• The supplied generic BA1 threshold is AF >= 0.05 under ACMG/AMP 2015 (PMID:25741868).
• Supplemental non-cancer observations are below BA1: gnomAD v2.1 non-cancer exomes AF 4.220264019717074e-06 and gnomAD v3.1 non-cancer genomes AF 6.758857482731119e-06.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but does not provide a usable population-specific BS1 threshold or source override, so the supplied generic SVI threshold applies. The highest observed all-comers gnomAD v4.1 population frequency is 3.813404200507098e-05, with overall AF 2.7879279004672568e-05 and 0 homozygotes, which is below the generic BS1 threshold of 0.01. The supplemental non-cancer frequencies are likewise below threshold (gnomAD v2.1 non-cancer exomes AF 4.220264019717074e-06; gnomAD v3.1 non-cancer genomes AF 6.758857482731119e-06).

Rule

Generic SVI BS1 threshold: allele frequency >= 0.01; no applicable MUTYH-specific override was available.

Evidence considered

• The InSiGHT MUTYH Version 1.0 framework was checked first; its retrieved rule payload contains no population-specific BS1 threshold or population-source override.
• gnomAD v4.1 reports overall AF 2.7879279004672568e-05 and maximum named-subpopulation AF 3.813404200507098e-05 in European (non-Finnish) individuals, with 0 homozygotes.
• The supplied generic SVI BS1 threshold is AF >= 0.01, with per-gene derivation preferred; the case provides no applicable gene-specific derivation. The supplied threshold block identifies Whiffin et al. 2017 (PMID:28518168) as the generic-default source.
• Supplemental non-cancer observations are below BS1: gnomAD v2.1 non-cancer exomes AF 4.220264019717074e-06 and gnomAD v3.1 non-cancer genomes AF 6.758857482731119e-06.

Sources

Reasoning

The variant has no observed homozygotes in gnomAD v2.1 or v4.1, and the available non-cancer gnomAD subsets also report 0 homozygotes. Because BS2 requires observation of the variant in an unaffected adult in a genotype or inheritance context inconsistent with disease, absence of homozygotes does not satisfy BS2; no qualifying healthy-homozygote observation is available.

Rule

BS2 requires a qualifying observation in an unaffected adult inconsistent with the disease model; absence of homozygotes is not sufficient.

Evidence considered

• The InSiGHT MUTYH Version 1.0 framework was checked first; its retrieved rule payload contains no usable BS2-specific population rule.
• gnomAD v2.1 reports 0 homozygotes, and gnomAD v4.1 reports 0 homozygotes for the variant.
• The supplemental non-cancer subsets also report 0 homozygotes: gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
• No qualifying observation of the variant in an unaffected adult as a homozygote or otherwise disease-inconsistent genotype is available.

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact-match ClinVar audit reports zero expert-panel submissions and no Benign or Likely benign expert-panel classification. The available ordinary laboratory submissions are Pathogenic or Likely pathogenic and cannot trigger BP6; aggregate ClinVar labels and non-expert assertions are excluded.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• The exact-match ClinVar audit reports expert_panel_submissions = 0 for the variant record.
• The reported laboratory classifications are Pathogenic or Likely pathogenic, not an expert-panel Benign or Likely benign assertion; such submissions cannot trigger BP6.

Sources

Reasoning

PS2 cannot be assessed. The case materials do not document a confirmed de novo occurrence of NM_001128425.2:c.309G>A (p.Trp103Ter) in an affected proband with confirmed maternity and paternity and negative parental testing. The MUTYH specification is present but provides no criterion-specific PS2 rule in the available ruleset. A de novo claim would require explicit proband phenotype, parental genotypes, and parentage confirmation.

Evidence considered

• The available InSiGHT MUTYH specification identifies autosomal recessive familial adenomatous polyposis 2 but contains no criterion-specific PS2 rule.
• No case-level parental testing, parentage confirmation, or affected-proband de novo observation is documented in the reviewed evidence.

Still missing

• Affected-proband phenotype and clinical context are not documented for this variant.
• Maternal and paternal testing results are not documented.
• Confirmed maternity and paternity are not documented.

Sources

Reasoning

The governing InSiGHT MUTYH specification is present but contains no criterion-specific functional rules. The variant is a transcript-confirmed nonsense change, NM_001128425.2:c.309G>A (p.Trp103Ter), but the available literature does not report a functional assay on this exact variant. PMID:23108399 provides biological and assay evidence that other biallelic MUTYH variants impair 8-oxoG:A glycosylase activity and increase mutagenesis, yet it explicitly does not mention c.309G>A or p.Trp103Ter. A predicted truncating consequence and general MUTYH loss-of-function biology are insufficient by themselves for PS3, and no validated variant-specific assay with appropriate controls is available to calibrate PS3 strength.

Evidence considered

• The InSiGHT MUTYH Version 1.0 specification was reviewed first; its retrieved ruleset contains no criterion-specific PS3 calibration.
• The variant is a nonsense change predicted as p.Trp103Ter, but this computational consequence is not a functional assay result.
• PMID:23108399 reports defective MUTYH 8-oxoG:A glycosylase activity and increased mutagenesis for other biallelic MUTYH variants in patient-derived lymphoblastoid cell lines, but the paper does not mention c.309G>A or p.Trp103Ter.
• Because no exact-variant functional result with appropriate controls is available, PS3 is not assessed rather than inferred from another variant's classification or assay.

Still missing

• A validated functional study directly testing c.309G>A (p.Trp103Ter) is unavailable.
• Variant-specific assay controls, biological readouts, and replication data are unavailable.

Sources

Reasoning

The applicable MUTYH InSiGHT specification was retrieved but contains no criterion-level PS4 rule or threshold. The available literature packet identifies PMID:15761860 as a PS4 candidate and describes a 302-person Australian cohort (120 controls, 120 APC-negative adenomatous-polyposis patients, and 62 additional patients), but the available extract does not establish that the exact genomic variant NM_001128425.2:c.309G>A (equivalent ClinVar representation NM_001048174.2:c.225G>A, p.Trp75Ter) was observed in cases or provide variant-specific case-control counts, enrichment, odds ratio, or statistical significance. Therefore, PS4 cannot be adjudicated from the available exact-variant evidence.

Evidence considered

• The retrieved MUTYH InSiGHT specification is incomplete and provides no PS4 criterion-level rule or threshold.
• The available PMID:15761860 abstract snippet reports a 302-person study with 120 controls, 120 APC-negative adenomatous-polyposis patients, and 62 additional patients, but does not establish observation of this exact variant or provide variant-specific enrichment statistics.
• The case variant is NM_001128425.2:c.309G>A, encoding NP_001121897.1:p.(W103*); the ClinVar record uses an equivalent transcript representation, NM_001048174.2:c.225G>A (p.Trp75Ter).

Still missing

• Exact-variant case and control counts from a valid case-control study
• A governing PS4 threshold or sufficient statistics such as odds ratio and confidence interval

Reasoning

The applicable InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive, so PM3 would require affected-proband evidence showing this variant in a biallelic configuration, such as a confirmed pathogenic variant in trans or homozygosity. The available case evidence documents no affected proband, no second MUTYH variant, no parental testing, and no phase determination. Population observations and ClinVar classifications do not establish allelic configuration and cannot substitute for direct PM3 evidence.

Evidence considered

• The MUTYH InSiGHT specification identifies familial adenomatous polyposis 2 as an autosomal recessive condition.
• The available evidence contains no affected-proband observation, biallelic genotype, second pathogenic MUTYH allele, parental testing, or phase determination for NM_001128425.2:c.309G>A.
• ClinVar and population records report variant-level observations or classifications but do not establish this variant's phase or biallelic occurrence in an affected individual.

Still missing

• Affected-proband genotype and phenotype details are not documented.
• No second pathogenic or likely pathogenic MUTYH variant is documented.
• No parental testing or cis/trans phase determination is documented.

Sources

Reasoning

PM6 cannot be assessed. The case materials do not report an apparently de novo occurrence of NM_001128425.2:c.309G>A (p.Trp103Ter) in an affected proband when parental testing is absent or incomplete. No proband phenotype, family context, parental genotypes, or meiosis information is provided. The available MUTYH specification contains no criterion-specific PM6 rule.

Evidence considered

• The available InSiGHT MUTYH specification contains no criterion-specific PM6 rule.
• No case-level report establishes an apparently de novo occurrence or supplies the required proband and parental context.

Still missing

• Affected-proband phenotype and clinical context are not documented.
• Parental testing is not reported, including whether testing was absent or incomplete.
• Family structure and relevant meioses are not documented.

Sources

Reasoning

PP1 cannot be assessed. The reviewed materials do not provide affected or unaffected relatives, genotype–phenotype co-segregation, informative meioses, or a count of segregating meioses for NM_001128425.2:c.309G>A (p.Trp103Ter). The available MUTYH specification contains no criterion-specific PP1 rule. General reports of MUTYH disease or variant classification do not establish segregation for this variant.

Evidence considered

• The available InSiGHT MUTYH specification contains no criterion-specific PP1 rule.
• The reviewed case evidence provides no family-level genotypes, phenotypes, or informative meioses demonstrating segregation of this variant.

Still missing

• No affected-relative genotypes and phenotypes are documented.
• No unaffected-relative genotypes are documented.
• No informative meiosis count or segregation analysis is provided.

Sources

Reasoning

The applicable MUTYH InSiGHT specification was retrieved but contains no criterion-level PP4 rule. The case evidence identifies the gene and predicted truncating consequence but supplies no patient phenotype, clinical presentation, diagnostic features, or phenotype-specific match to MUTYH-associated polyposis. Gene-disease background alone is insufficient for PP4, so the criterion is not assessed.

Evidence considered

• The retrieved MUTYH InSiGHT specification is incomplete and provides no PP4 criterion-level rule.
• The case materials identify MUTYH and a nonsense consequence, but do not provide patient-level phenotype or diagnostic findings.

Still missing

• Patient phenotype and clinical diagnosis
• Phenotype-specific evidence linking the patient's findings to MUTYH-associated polyposis

Reasoning

The governing InSiGHT MUTYH specification is present but contains no criterion-specific functional rules. No validated benign functional study directly tested NM_001128425.2:c.309G>A (p.Trp103Ter), and the available functional paper PMID:23108399 reports damaging effects for other MUTYH variants rather than a normal assay result for this variant. Therefore, there is no well-established, biologically relevant assay showing preserved MUTYH function or otherwise supporting BS3 at any strength.

Evidence considered

• The InSiGHT MUTYH Version 1.0 specification was reviewed first; its retrieved ruleset contains no criterion-specific BS3 calibration.
• No source in the reviewed evidence reports preserved function for c.309G>A (p.Trp103Ter).
• PMID:23108399 is relevant to MUTYH functional biology but studied other biallelic variants and does not provide a benign result for this variant.
• Absence of a variant-specific benign assay cannot be converted into BS3 or used to infer benignity from population, computational, or clinical classification evidence.

Still missing

• A validated functional study directly testing c.309G>A (p.Trp103Ter) with a benign or functionally normal result is unavailable.
• Appropriate positive and negative controls and reproducible variant-specific functional measurements are unavailable.

Sources

Reasoning

BS4 cannot be assessed. The case materials do not identify an unaffected individual who carries NM_001128425.2:c.309G>A (p.Trp103Ter), nor do they provide age, phenotype ascertainment, penetrance context, or family segregation details needed to interpret non-segregation. The available MUTYH specification contains no criterion-specific BS4 rule.

Evidence considered

• The available InSiGHT MUTYH specification contains no criterion-specific BS4 rule.
• No unaffected carrier, adequate phenotype assessment, or family-level non-segregation evidence is documented.

Still missing

• No unaffected carrier is identified.
• No carrier age, clinical evaluation, or phenotype ascertainment is documented.
• No family-level non-segregation analysis or penetrance context is provided.

Sources

Reasoning

BP2 requires reliable co-occurrence of the evaluated variant with a pathogenic or likely pathogenic variant in the same gene or disease context, with phase and inheritance considered. The available evidence contains no individual-level co-occurrence record, no second MUTYH variant, and no cis/trans phase information. Therefore, absence of a documented co-occurrence cannot be treated as evidence that BP2 is met or not met.

Evidence considered

• No individual-level co-occurrence of NM_001128425.2:c.309G>A with another pathogenic or likely pathogenic MUTYH variant is documented.
• No cis/trans phase determination or inheritance data are available to evaluate a potential BP2 observation.
• Variant-level ClinVar classifications, population frequencies, and general MUTYH disease descriptions do not establish BP2 co-occurrence evidence.

Still missing

• No same-individual genotype record with another pathogenic or likely pathogenic variant is documented.
• No cis/trans phase information is documented.
• No inheritance or segregation data are documented for a potential co-occurring variant.

Reasoning

The applicable MUTYH InSiGHT specification was retrieved but contains no criterion-level BP5 rule. The available case evidence does not document a second pathogenic variant causing the same phenotype, a molecular diagnosis that explains the phenotype independently, or a validated co-occurrence/alternate-cause observation. No BP5 evidence can therefore be adjudicated.

Evidence considered

• The retrieved MUTYH InSiGHT specification is incomplete and provides no BP5 criterion-level rule.
• The available case materials do not document an alternate molecular cause or a relevant second pathogenic variant.

Still missing

• A documented alternate pathogenic variant or independent molecular diagnosis explaining the phenotype
• Relevant co-occurrence evidence and phenotype linkage