MUTYH c.925C>T, p.(Arg309Cys)

Reasoning

The MUTYH p.R309C variant was directly tested in a MutY-deficient E. coli complementation assay with wild-type comparison and protein-expression assessment. It produced a rifampicin-resistant mutation rate 2.9-fold above wild type and was categorized by the investigators as partially defective, supporting abnormal MUTYH function. The assay is biologically relevant to MUTYH base-excision repair, but the result is partial rather than a clearly null defect and another publication reports normal glycosylase activity, so supporting strength is appropriate and the discordance warrants review.

Evidence considered

• The governing source is the ClinGen InSiGHT MUTYH specification (Version 1.0); the case bundle identifies it as applicable, but its extracted rule payload is empty and does not provide a PS3-specific strength calibration.
• PMID:25820570 directly tested p.R309C (listed as c.883C>T in the paper's NM_001048171.1 reference system) in a MutY-disrupted E. coli complementation assay. The reported rifampicin-resistant mutation rate was 27.7 per 10^8, or 2.9-fold the wild-type rate, with normalized protein level 0.52; the authors categorized the variant as partially defective.
• The PMID:25820570 assay measured a MUTYH-relevant DNA-repair phenotype in a MutY-deficient background, used wild-type comparison, and included western-blot protein-expression assessment, supporting biological relevance and assay controls.
• PMID:22297469 states that p.Arg309Cys had normal glycosylase activity in one previously published functional study. This is variant-specific but is a secondary report without the primary assay details in the extracted record, and it conflicts with the partial defect observed in PMID:25820570.

Still missing

• No independent replication of the exact variant's functional result in a validated human-cell or orthogonal assay was identified in the extracted evidence.
• The functional literature is discordant: the E. coli complementation assay reports partial dysfunction, whereas a cited glycosylase study is described as normal; assay-specific calibration and quantitative thresholds for PS3 strength are not provided by the MUTYH specification artifact.

Sources

Reasoning

PM2 is not met because the variant is observed in population databases and in published control data. gnomAD v4.1 reports 1121 alternate alleles and one homozygote; gnomAD v2.1 reports 133 alternate alleles. PMID:22297469 also reports the variant in 9/1,270 controls. These observations are incompatible with an absent-from-controls PM2 assertion.

Rule

Generic fallback: PM2 requires absence or sufficiently rare representation in population controls; a variant with multiple population observations and a reported homozygote does not meet PM2.

Evidence considered

• The governing InSiGHT MUTYH CSPEC record is present, but no operational PM2 rule was captured; the generic absence-from-controls requirement was therefore used.
• gnomAD v4.1 reports AF 0.00069446, 1121 alternate alleles, and one homozygote.
• gnomAD v2.1 reports AF 0.000470443 and 133 alternate alleles.
• PMID:22297469 reports p.Arg309Cys in 9/1,270 Dutch controls (0.7%).
• PMID:19032956 identifies c.925C>T/p.R309C once among 370 mutations in a MUTYH-associated polyposis cohort; this is a disease-cohort observation, not control evidence, but it was reviewed for population/ascertainment context.

Sources

Reasoning

NM_001128425.2:c.925C>T is a missense variant encoding p.(Arg309Cys), so only the calibrated missense (REVEL) path is applicable. REVEL is 0.592, within the generic gray zone (0.250–0.750), and therefore does not meet PP3.

Rule

Generic ACMG/AMP calibrated missense computational-evidence fallback: REVEL >0.750 for PP3; REVEL 0.250–0.750 yields neither PP3 nor BP4 (threshold calibration: PMID:36413997).

Evidence considered

• The governing MUTYH InSiGHT CSPEC was reviewed; its available ruleset has no PP3 or BP4 criterion-specific rule or pre-assigned lookup result for this variant, so the generic calibrated missense path applies.
• The variant consequence is missense, NP_001121897.1:p.(Arg309Cys), and the available REVEL score is 0.592.
• Under the generic missense calibration, REVEL >0.750 supports PP3 and REVEL <0.250 supports BP4; REVEL 0.592 is in the gray zone. The published calibration source is PMID:36413997.
• SpliceAI max delta 0.074 was not used because splice prediction is not the applicable computational mechanism for this missense substitution. BayesDel was not used because no verified published calibration threshold is available to this pipeline.

Sources

Reasoning

PP5 is not applied because no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is documented. The retrieved ClinVar record is explicitly flagged as a non-exact transcript/HGVS match and has no expert-panel submissions.

Rule

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

Evidence considered

• The ClinVar retrieval identifies the returned record as NM_001048174.2:c.841C>T (p.Arg281Cys), not the queried NM_001128425.2:c.925C>T (p.Arg309Cys), and marks it as no_exact_match.
• The submission audit summary reports zero expert-panel submissions; ordinary laboratory classifications and aggregate labels were not used.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion would be required to apply PP5 under the specified rule.

Sources

Reasoning

BA1 is not met. The variant is present in gnomAD v4.1 at an overall allele frequency of 0.06945% (1121/1,614,204 alleles), with a maximum reported population frequency of 0.08830% in non-Finnish Europeans; both are far below the generic BA1 threshold of >1%. The gnomAD v2.1 frequency is likewise low at 0.04704% overall and 0.09064% in non-Finnish Europeans.

Rule

Generic fallback: BA1 requires a population allele frequency >1%; no operational MUTYH-specific CSPEC rule was available in the captured framework.

Evidence considered

• The governing InSiGHT MUTYH CSPEC record is present, but its captured rule payload is empty and the framework is marked incomplete; therefore no population-specific BA1 threshold could be applied from the specification.
• Generic population threshold used because the applicable specification did not provide an operational rule in the case bundle: BA1 requires an allele frequency greater than 1%.
• gnomAD v4.1 reports AF 0.00069446 (1121/1614204 alleles), maximum population AF 0.000883025 in non-Finnish Europeans, and one homozygote.
• gnomAD v2.1 reports AF 0.000470443 (133/282712 alleles), maximum population AF 0.000906429 in non-Finnish Europeans, and zero homozygotes.

Sources

Reasoning

BS1 is not met. The observed population frequencies are below the generic BS1 threshold of >0.3%: gnomAD v4.1 overall AF is 0.06945% and its highest population AF is 0.08830% in non-Finnish Europeans; gnomAD v2.1 overall AF is 0.04704% and its highest population AF is 0.09064%. An independent Dutch case-control study reported the variant in 9/1,270 controls (0.7%), but this does not establish that the variant exceeds the applicable disease-specific maximum credible frequency for MUTYH-associated polyposis and is discordant with the larger reference-population datasets.

Rule

Generic fallback: BS1 requires AF >0.3% and an allele frequency higher than expected for the disease; no operational MUTYH-specific CSPEC rule was available in the captured framework.

Evidence considered

• The governing InSiGHT MUTYH CSPEC record is present, but the captured rule payload is empty and marked incomplete; no gene-specific BS1 rule was available to supersede the generic fallback.
• Generic population threshold used because no operational VCEP threshold was available: BS1 requires an allele frequency >0.3% when the frequency is higher than expected for the disorder.
• gnomAD v4.1 reports overall AF 0.06945% and maximum population AF 0.08830% in non-Finnish Europeans.
• gnomAD v2.1 reports overall AF 0.04704% and maximum population AF 0.09064% in non-Finnish Europeans.
• PMID:22297469 directly reports p.Arg309Cys in 9/1,270 Dutch controls (0.7%), but the study is not a validated MUTYH-associated polyposis maximum-frequency analysis and its control estimate is not used to override the larger gnomAD datasets.

Still missing

• No operational MUTYH-specific maximum credible allele-frequency threshold or penetrance model was supplied by the incomplete CSPEC payload.

Sources

Reasoning

BS3 is not met because the strongest directly extracted assay evidence for p.R309C shows a partially defective MUTYH phenotype rather than normal function. Although PMID:22297469 reports that a prior glycosylase study found normal activity, this isolated secondary report does not establish a reproducibly well-calibrated benign functional result and conflicts with the direct complementation assay.

Evidence considered

• PMID:25820570 directly reports a 2.9-fold elevation in the MutY-deficient E. coli mutation rate for p.R309C relative to wild type and categorizes the variant as partially defective; this argues against a benign functional result.
• PMID:22297469 reports: "The variant, p.Arg309Cys, has been described as a VUS in polyposis patients [6, 27]. Its effect was tested in one functional study, and showed normal glycosylase activity [28]." The cited normal result is secondary in this paper and lacks the primary assay details in the extracted record.
• The available evidence is therefore insufficient for BS3, especially because the exact-variant results are discordant and no validated BS3 calibration is supplied by the applicable MUTYH specification artifact.

Still missing

• A fully validated, independently replicated assay demonstrating normal MUTYH function for the exact variant, with defined positive and negative controls and a calibrated benign threshold, was not identified.
• The primary source and detailed methods for the normal glycosylase result referenced by PMID:22297469 were not available in the extracted evidence.

Sources

Reasoning

NM_001128425.2:c.925C>T is a missense variant encoding p.(Arg309Cys), so only the calibrated missense (REVEL) path is applicable. REVEL is 0.592, within the generic gray zone (0.250–0.750), and therefore does not meet BP4.

Rule

Generic ACMG/AMP calibrated missense computational-evidence fallback: REVEL <0.250 for BP4; REVEL 0.250–0.750 yields neither PP3 nor BP4 (threshold calibration: PMID:36413997).

Evidence considered

• The governing MUTYH InSiGHT CSPEC was reviewed; its available ruleset has no PP3 or BP4 criterion-specific rule or pre-assigned lookup result for this variant, so the generic calibrated missense path applies.
• The variant consequence is missense, NP_001121897.1:p.(Arg309Cys), and the available REVEL score is 0.592.
• Under the generic missense calibration, REVEL >0.750 supports PP3 and REVEL <0.250 supports BP4; REVEL 0.592 is in the gray zone. The published calibration source is PMID:36413997.
• SpliceAI max delta 0.074 was not used because splice prediction is not the applicable computational mechanism for this missense substitution. BayesDel was not used because no verified published calibration threshold is available to this pipeline.

Sources

Reasoning

BP6 is not applied because no exact-variant ClinVar expert-panel Benign or Likely benign assertion is documented. The retrieved ClinVar record is explicitly a non-exact match and has no expert-panel submissions.

Rule

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

Evidence considered

• The retrieved ClinVar title is NM_001048174.2:c.841C>T (p.Arg281Cys), which does not match the queried NM_001128425.2:c.925C>T (p.Arg309Cys).
• Although the returned non-exact record includes ordinary laboratory Likely benign submissions, it has zero expert-panel submissions; these non-expert assertions were not used.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign assertion would be required to apply BP6 under the specified rule.

Sources

Reasoning

The variant is NM_001128425.2:c.925C>T, p.Arg309Cys (p.R309C). The reviewed literature confirms this exact variant, but no source provides a pathogenic same-amino-acid substitution at Arg309 that would satisfy PS1. The available MUTYH VCEP framework is present but unstructured and does not supply an applicable PS1 rule or comparator list.

Evidence considered

• The governing source is the InSiGHT MUTYH specification, version 1.0, but its extracted rule payload is empty and framework_complete is false.
• PMID:19032956 lists the exact variant c.925C>T, p.R309C once, without variant-specific classification or functional evidence; it does not report an alternative change at Arg309.
• PMID:25820570 reports p.R309C in a different MUTYH transcript/reference system as c.883C>T and does not provide a pathogenic same-amino-acid comparator.
• PMID:22297469 reports p.Arg309Cys as a VUS and discusses normal glycosylase activity, but does not establish PS1.

Still missing

• A clinically established pathogenic or likely pathogenic alternative nucleotide change producing p.Arg309Cys at the same codon is not documented in the supplied evidence.
• A complete MUTYH VCEP PS1 rule/comparator list is unavailable in the supplied framework materials.

Sources

Reasoning

No proband-level de novo observation is documented for NM_001128425.2:c.925C>T (p.Arg309Cys). The bundle contains no parental genotypes, maternity/paternity confirmation, or statement that the variant was absent in both tested parents; therefore PS2 cannot be applied.

Rule

Apply PS2 only when the variant is confirmed de novo in the proband with verified maternity and paternity; the available case evidence does not establish this.

Evidence considered

• The MUTYH InSiGHT specification is present, but its extracted rule payload is empty and it provides no case-specific PS2 rule or evidence.
• The case bundle provides no parental-testing, trio, de novo, maternity, or paternity data for this variant.

Still missing

• Documented proband phenotype and the clinical indication
• Variant testing results for both biological parents
• Confirmation of maternity and paternity and assay quality
• Evidence that the variant is absent from both parents

Sources

Reasoning

No qualifying case-control enrichment for MUTYH-associated polyposis/familial adenomatous polyposis 2 was identified for c.925C>T (p.Arg309Cys). The available exact-variant reports do not provide a controlled enrichment analysis for the relevant recessive colorectal polyposis phenotype.

Rule

Apply PS4 only when the exact variant has robust statistically significant enrichment in affected cases over appropriately matched controls for the applicable MUTYH-associated recessive polyposis phenotype.

Evidence considered

• The MUTYH InSiGHT CSPEC identifies the applicable disease context as autosomal-recessive familial adenomatous polyposis 2, but no criterion-specific PS4 rule was retrievable from the supplied framework payload.
• PMID:19032956 reports p.R309C once in a MUTYH-associated polyposis cohort, without variant-specific case-control data or clinical details sufficient to assess enrichment.
• PMID:25820570 lists p.R309C as previously reported in AFAP (2 reports) and multiple polyps (2 reports), but supplies no control group, zygosity/phase data, or enrichment statistic.
• PMID:22297469 is a breast-cancer case-control study rather than a study of the applicable colorectal-polyposis phenotype; its reported association was not statistically significant (OR 2.19, 95% CI 0.81–5.89; p=0.15).

Still missing

• A phenotype-matched, appropriately controlled case-control study reporting c.925C>T (p.Arg309Cys) carrier counts and statistical analysis is needed.
• The zygosity, phase, and phenotype of the single p.R309C observation in the MUTYH-associated polyposis cohort are not provided in the extracted evidence.

Sources

Reasoning

The supplied vcep_materials.json has an empty domain_tables object. Therefore, no authoritative complete MUTYH critical-domain list is available for checking residue 309. The flattened/extracted CSPEC ruleset is incomplete and contains no usable PM1 domain rule. The absence of a supplied domain table is insufficient to conclude that PM1 is not met.

Evidence considered

• vcep_materials.json reports domain_tables as an empty object and the extracted MUTYH framework as framework_complete=false with an empty rule_payload.
• The supplied evidence reports no statistically significant cancer hotspot for MUTYH R309, but hotspot absence does not substitute for an authoritative VCEP domain assessment.

Still missing

• Authoritative MUTYH VCEP domain-table entries and residue boundaries are not present in vcep_materials.json.
• No complete criterion-specific CSPEC PM1 rule or approved critical functional-domain list is available for residue 309.

Sources

Reasoning

The governing InSiGHT MUTYH specification identifies autosomal recessive inheritance, but the available evidence does not document that NM_001128425.2:c.925C>T (p.Arg309Cys) occurred in an affected individual with a pathogenic or likely pathogenic MUTYH variant in trans. PMID:19032956 reports the exact variant once in a MUTYH-associated polyposis cohort without genotype, phase, or variant-specific clinical details. PMID:25820570 reports the same protein change in AFAP/multiple-polyp reports but does not establish an affected proband with a second pathogenic allele in trans. General reports of biallelic MUTYH disease cannot be transferred to this exact variant without phase information.

Rule

Apply the governing MUTYH InSiGHT autosomal-recessive framework; PM3 requires variant-specific affected-proband evidence with a pathogenic/likely pathogenic second MUTYH allele demonstrated in trans. No criterion-specific CSPEC calibration was available in the bundle.

Evidence considered

• The InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification (version 1.0) names autosomal recessive inheritance, but the bundled ruleset contains no explicit PM3 calibration or criterion-specific rule payload.
• PMID:19032956 lists c.925C>T, p.R309C once among 370 MUTYH mutations in a multicenter cohort of 257 patients with MUTYH-associated polyposis; the extracted paper finding states that no variant-specific clinical, functional, segregation, or phase data were provided.
• PMID:25820570 explicitly studies p.R309C in a MutY-deficient E. coli complementation assay and notes prior reports in AFAP and multiple-polyps cases, but the extracted evidence does not identify an affected proband carrying a second pathogenic MUTYH allele in trans.
• PMID:16557584 documents the general pattern that disease-associated MUTYH missense variants occurred biallelically or with another presumed pathogenic mutation, but it does not mention p.R309C and therefore cannot establish PM3 for this variant.

Still missing

• A documented affected-proband observation for p.Arg309Cys is needed.
• The identity and pathogenicity of the second MUTYH allele are not documented for an exact-variant case.
• Phase testing or unequivocal parental/family data establishing the two alleles in trans is absent.

Sources

Reasoning

No pathogenic or likely pathogenic missense variant at Arg309, other than the target p.Arg309Cys itself, is identified in the supplied evidence. The PM5 candidate artifact contains zero same-residue candidates and explicitly states that classic PM5 semantics could not be confirmed safely. The target variant's own reports and functional assay cannot serve as an alternate same-residue comparator.

Evidence considered

• The supplied PM5 summary reports zero same-residue candidates and recommends not applying PM5 from that artifact alone.
• PMID:19032956 identifies p.R309C itself but reports no other Arg309 missense variant.
• PMID:25820570 functionally studies p.R309C itself, not an alternate substitution at Arg309.
• PMID:22297469 reports p.Arg309Cys itself and does not provide an alternate Arg309 pathogenic variant.

Still missing

• A validated pathogenic or likely pathogenic alternate missense change at MUTYH residue Arg309 is not documented in the supplied evidence.
• The governing VCEP PM5 rule and any complete comparator set are unavailable.

Sources

Reasoning

No reliable report of presumed de novo occurrence is available for c.925C>T (p.Arg309Cys). The literature extraction identifies the variant in observational cohorts, but does not report parental testing, a de novo assertion, or sufficient family context to treat any occurrence as presumed de novo.

Rule

Apply PM6 only for a presumed de novo occurrence without confirmed parentage; a report of the variant in an affected individual or cohort is insufficient by itself.

Evidence considered

• The extracted finding for PMID:19032956 records c.925C>T/p.R309C once among 370 MUTYH mutations but explicitly states that variant-specific clinical, functional, segregation, and population data were not provided.
• The extracted finding for PMID:25820570 reports p.R309C in individuals with attenuated FAP or multiple polyps and in a functional assay, but gives no parental testing or presumed-de-novo information.
• The extracted finding for PMID:22297469 reports heterozygous p.Arg309Cys observations in breast-cancer and control cohorts, but gives no family or parental-testing evidence.
• The MUTYH InSiGHT specification is present, but its extracted rule payload is empty and provides no usable PM6-specific rule.

Still missing

• A case report or cohort record identifying the proband carrying the variant
• Parental availability and testing status for that proband
• Explicit documentation that the occurrence was presumed de novo despite unconfirmed parentage

Sources

Reasoning

No informative familial segregation data are provided. The available extracted publications report isolated cohort observations or variant counts, without affected and unaffected relatives, phase, number of informative meioses, or quantitative cosegregation analysis; PP1 cannot be applied.

Rule

Apply PP1 only when the variant cosegregates with disease in informative relatives/meioses, with strength determined by the applicable specification or validated quantitative framework; no such data are available.

Evidence considered

• The extracted finding for PMID:19032956 states that p.R309C was observed once in the cohort and that no variant-specific clinical or segregation data were provided.
• The extracted finding for PMID:25820570 lists p.R309C among reports in individuals with attenuated FAP or multiple polyps, but does not provide family genotypes, affected-relative transmission, or meioses.
• The extracted finding for PMID:22297469 describes heterozygous carrier frequencies in breast-cancer, BRCAx, and control groups, not cosegregation within families.
• The MUTYH InSiGHT specification is present, but its extracted rule payload is empty and provides no usable PP1-specific rule.

Still missing

• Pedigree with affected and unaffected relatives
• Genotypes and phenotypes for informative relatives
• Phase of c.925C>T relative to any second MUTYH variant
• Number of informative meioses and segregation likelihood or other quantitative analysis

Sources

Reasoning

MUTYH is a DNA glycosylase and pathogenic missense variants are reported, but the supplied evidence does not establish the generic PP2 requirement that missense variation is a common disease mechanism for this gene together with a low benign missense rate. The MUTYH VCEP extraction does not provide a PP2 rule or quantitative gene-level missense framework.

Evidence considered

• PMID:26377631 describes MUTYH biochemical function and experimentally characterizes several other missense variants, but does not establish the gene-level PP2 missense-rate requirements for this variant.
• PMID:16557584 reports disease-associated MUTYH missense variants at conserved sites, but does not provide the required benign-missense depletion analysis.
• PMID:25741868 provides general ACMG/AMP guidance but does not supply MUTYH-specific PP2 evidence.

Still missing

• No applicable MUTYH-specific PP2 rule is available.
• No complete gene-level analysis demonstrating both a dominant missense disease mechanism for the relevant condition and a low benign missense rate is supplied.

Sources

Reasoning

No phenotype, clinical findings, or biallelic MUTYH genotype/phase information for the individual being interpreted is present in the evidence bundle. Therefore, phenotype specificity for MUTYH-associated polyposis cannot be evaluated.

Rule

Apply PP4 only when the observed individual phenotype is highly specific for the applicable MUTYH-associated condition after considering the gene's recessive inheritance and reasonable alternative causes.

Evidence considered

• The applicable MUTYH InSiGHT CSPEC disease context is autosomal-recessive familial adenomatous polyposis 2.
• The supplied case evidence contains no proband phenotype or individual-level clinical diagnosis from which to establish a highly specific phenotype.

Still missing

• Individual-level phenotype details, including adenoma burden, colorectal cancer history, age at onset, and exclusion of alternative etiologies, are needed.
• Biallelic MUTYH status and phase, if present, are needed to assess consistency with the autosomal-recessive disease mechanism.

Sources

Reasoning

BS2 cannot be established from the available evidence. gnomAD v4.1 reports one homozygote, but gnomAD does not document that this individual is a well-phenotyped healthy adult free of MUTYH-associated polyposis or relevant disease, and the case bundle provides no phenotype, age, ascertainment, or clinical follow-up for that homozygote. The absence of homozygotes in gnomAD v2.1 is not sufficient to apply BS2.

Rule

Generic BS2 requires observation of the variant in a healthy adult or healthy adults in a state expected to be affected by a highly penetrant disorder; a database homozygote without documented phenotype and age is insufficient.

Evidence considered

• The governing InSiGHT MUTYH CSPEC record is present but contains no operational BS2 rule in the captured payload.
• gnomAD v4.1 reports one homozygote among 1,614,204 alleles, including one homozygote in the non-Finnish European population; the dataset extract supplies no individual-level phenotype or age information.
• gnomAD v2.1 reports zero homozygotes, which neither supports nor excludes BS2.

Still missing

• Clinical phenotype and age information for the single gnomAD v4.1 homozygote are unavailable.
• No confirmed healthy-adult homozygote or disease-relevant biallelic observation with adequate phenotype exclusion was supplied.

Sources

Reasoning

No documented unaffected relative who is expected to carry the variant is reported, and no family-level non-segregation analysis is available. Population observations and the absence of variant-specific family data do not establish BS4.

Rule

Apply BS4 only when the variant is shown not to segregate with disease in an informative family; the available evidence contains no such family analysis.

Evidence considered

• The extracted finding for PMID:19032956 provides a cohort mutation count only and explicitly reports no variant-specific segregation data.
• The extracted finding for PMID:25820570 reports affected-person observations and functional testing, but no unaffected relatives or non-segregation results.
• The extracted finding for PMID:22297469 provides case-control carrier frequencies, which are not evidence of familial non-segregation.
• The MUTYH InSiGHT specification is present, but its extracted rule payload is empty and provides no usable BS4-specific rule.

Still missing

• A pedigree with clinically informative unaffected relatives
• Genotypes of unaffected relatives expected to carry the variant
• Adequate age and phenotype assessment of those relatives
• A documented non-segregation analysis excluding phenocopy, reduced penetrance, and misclassification

Sources

Reasoning

MUTYH-associated polyposis is recessive and loss-of-function biology is well established, but the supplied evidence also documents disease-associated missense variation and does not establish that missense variants are generally benign in MUTYH. The incomplete MUTYH VCEP framework provides no applicable BP1 rule or gene-level missense-benign analysis.

Evidence considered

• PMID:16557584 describes biallelic MUTYH disease and reports disease-associated missense variants, so it does not support a blanket benign-missense presumption.
• PMID:26377631 experimentally evaluates MUTYH missense variants in biochemical assays, demonstrating that missense variation is biologically relevant to the gene, although it does not assess p.R309C.
• PMID:25820570 reports p.R309C as partially defective in a MutY-deficient E. coli complementation assay, which argues against applying BP1 solely from the gene's loss-of-function mechanism; this result is not used as a standalone pathogenic classification.

Still missing

• No applicable MUTYH-specific BP1 rule is available.
• No comprehensive evidence demonstrates that missense variation is not a disease mechanism for MUTYH or that MUTYH missense variants are generally benign.

Sources

Reasoning

No reliable phase-resolved observation supports the benign allelic evidence criterion. The available exact-variant reports do not show p.Arg309Cys in trans with a pathogenic MUTYH variant in a recessive context, nor in cis with a pathogenic variant in a context where that observation would support BP2. Population carrier observations and an unphased report of the variant are insufficient to apply BP2.

Rule

Apply the governing MUTYH InSiGHT autosomal-recessive framework; BP2 requires a documented phase-resolved allelic configuration relevant to the criterion. The available CSPEC payload has no explicit BP2 calibration, and the case bundle lacks such phase evidence.

Evidence considered

• The governing InSiGHT MUTYH specification establishes autosomal recessive inheritance, but the bundled ruleset provides no explicit BP2-specific calibration.
• PMID:19032956 reports the exact p.R309C variant once in a MAP cohort without phase or a second-allele description.
• PMID:22297469 reports heterozygous p.Arg309Cys carriers in breast-cancer, BRCAx, and control cohorts and describes the variant as a VUS; the extracted finding provides no cis/trans information and therefore does not satisfy an allelic BP2 observation.
• PMID:25820570 reports p.R309C in AFAP and multiple-polyps cases and functional assay results, but no phase-resolved observation with a pathogenic allele is provided.

Still missing

• No documented phase between p.Arg309Cys and another pathogenic or likely pathogenic MUTYH variant.
• No variant-specific family or proband record demonstrates the allelic configuration required for BP2.
• The available breast-cancer cohort observations are unphased carrier observations and do not establish BP2.

Sources

Reasoning

No individual-level phenotype, molecular diagnosis, or evidence of an alternative molecular cause is available. BP5 cannot be assessed.

Rule

Apply BP5 only when an alternative molecular cause has been established for the individual's phenotype, making the assessed variant non-contributory to that phenotype.

Evidence considered

• The applicable framework describes autosomal-recessive MUTYH-associated familial adenomatous polyposis 2, but the bundle provides no proband-level alternate diagnosis or phenotype explanation.

Still missing

• A documented individual phenotype and a confirmed alternative molecular diagnosis that fully explains that phenotype are needed.

Sources