MUTYH c.1187G>A, p.(Gly396Asp)

Reasoning

PS3 is met at moderate strength. The exact p.G396D variant was tested in a MutY-deficient E. coli complementation assay using nine independent overnight cultures, with empty-vector and wild-type controls. Relative to wild-type MUTYH, p.G396D produced a 1.7-fold higher rifampicin-resistant mutation rate and was classified by the study's prespecified assay calibration as partially defective; the same study confirmed normal protein expression and nuclear localization, supporting a specific BER functional defect rather than absent expression or mistargeting. Independent functional evidence summarized in a review reports approximately 50% of wild-type mismatched-substrate binding and reduced repair rates in human cell lines with biallelic G396D, plus an 86% reduction in adenine removal and a six-fold slower removal rate in the corresponding E. coli MutY assay. The assays are biologically relevant to MUTYH base-excision repair and include appropriate wild-type, empty-vector, and expression controls, but the primary complementation result is partial rather than a complete loss of function and the additional human-cell evidence is reported through a review, so moderate rather than strong strength is calibrated.

Evidence considered

• The MUTYH InSiGHT/ClinGen specification was identified as governing, but its retrieved rule payload contained no criterion-specific PS3 strength rule; generic ACMG/AMP functional calibration was therefore used as fallback.
• PMID:25820570 tested the exact p.G396D variant in MutY-deficient E. coli, comparing wild-type MUTYH with an empty-vector control; nine independent overnight cultures were analyzed for rifampicin-resistant mutations.
• In PMID:25820570, wild-type MUTYH reduced the mutation rate to 9.67 per 10^8 versus 137 per 10^8 for empty vector, while p.G396D had a 1.7-fold higher mutation rate than wild type and was classified as partially defective using the study's stated 1.7-fold boundary.
• PMID:25820570 additionally found minimal differences in MUTYH protein expression and similar nuclear localization across variants, supporting a functional BER defect rather than loss of protein expression or cellular targeting.
• PMID:19506731 reports that human cell lines with biallelic G396D had about 50% of wild-type mismatched-substrate binding and lower repair rates, with equivalent MUTYH protein levels; the review also reports an 86% reduction in adenine removal and a six-fold slower rate for the corresponding E. coli MutY variant.
• The functional readouts directly measure MUTYH-mediated oxidative-DNA-damage repair, the established biological function relevant to MUTYH-associated polyposis.

Still missing

• No MUTYH-specific VCEP PS3 strength rule was available in the retrieved specification.
• The primary exact-variant complementation result demonstrates partial rather than complete loss of function; a fully quantitative, independently replicated human-cell assay would improve strength calibration.

Sources

Reasoning

The governing MUTYH framework is available but unstructured and provides no domain_tables entry. Independent functional literature identifies the MUTYH C-terminal domain as responsible for 8-oxo-guanine recognition and binding and base flipping, placing residue 396 within a biologically critical domain; the exact p.G396D variant is reported to impair mismatched-substrate binding and repair. This supports PM1 at supporting strength, without upgrading it because the extracted VCEP domain table is empty and no formal residue boundaries are supplied.

Rule

Generic PM1 supporting is applicable when a variant lies in a well-established critical functional domain; no VCEP domain-table rule or upgrade was available.

Evidence considered

• The MUTYH InSiGHT framework governs this case, but its extracted domain_tables object is empty, so no authoritative VCEP domain boundary can be applied.
• PMID:19506731 states that G396D is located in the MUTYH C-terminal domain responsible for 8-oxo-guanine recognition and binding and base flipping, and reports reduced substrate binding and repair in biallelic G396D cell lines.
• PMID:25820570 describes glycine 396 as contributing to 8-oxoG:A mismatch recognition and MUTYH conformational flexibility and categorizes p.G396D as partially defective in a MutY-deficient complementation assay.

Sources

Reasoning

The variant is missense (NM_001128425.2:c.1187G>A, p.Gly396Asp), so the missense REVEL path applies and SpliceAI is not used. REVEL is 0.954, meeting the generic ClinGen SVI strong PP3 threshold of >=0.932 from Pejaver et al. 2022 (PMID:36413997). The MUTYH VCEP framework was reviewed first but contains no applicable PP3/BP4-specific rule, so the supplied generic calibration applies.

Rule

Missense REVEL: PP3 strong at >=0.932; use REVEL only and do not use SpliceAI for this missense consequence.

Evidence considered

• The variant consequence is missense, p.Gly396Asp; therefore REVEL is the sole applicable computational path for PP3/BP4.
• Local REVEL lookup reports a score of 0.954.
• ClinGen SVI REVEL calibration specifies strong PP3 at >=0.932 (Pejaver et al. 2022, PMID:36413997).
• The MUTYH VCEP framework was reviewed first; its available rule payload contains no applicable PP3/BP4-specific assignment, so the supplied generic calibration was used.

Sources

Reasoning

The governing InSiGHT/MUTYH framework is present but incomplete and provides no usable PM2 threshold, so the supplied generic SVI threshold applies. The relevant non-cancer v2.1 exome AF is 0.00295109 (695/235506 alleles; 3 homozygotes), and gnomAD v4.1 total AF is 0.00473005 (7634/1613938 alleles; 26 homozygotes). Both substantially exceed the generic PM2 supporting threshold of <=0.0001 (ClinGen SVI recommendation, PMID:25741868). Therefore PM2 is not met.

Rule

Generic ClinGen-SVI PM2 supporting threshold <=0.0001, used because no usable MUTYH-specific rule is available.

Evidence considered

• The InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification (version 1.0) is available, but its ruleset is incomplete and contains no usable PM2 threshold or population-source instruction.
• Following the requested source hierarchy, the non-cancer v2.1 exome result is considered: AF 0.00295109 from 695/235506 alleles, with 3 homozygotes.
• The non-cancer v3.1 result is AF 0.00330486 from 489/147964 alleles, with 1 homozygote; v3 has no exome cohort.
• The default all-comers gnomAD v4.1 result is also present at AF 0.00473005 from 7634/1613938 alleles, with 26 homozygotes.
• The supplied generic PM2 supporting threshold is <=0.0001 (ClinGen SVI recommendation, PMID:25741868); all available population frequencies exceed it.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The ClinVar record has no expert-panel submissions, is reported as criteria provided by multiple submitters or single laboratories, and the record identity itself maps to c.1103G>A/p.Gly368Asp rather than the assessed c.1187G>A/p.Gly396Asp. Therefore no qualifying exact-variant expert-panel assertion triggers PP5.

Rule

PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• The ClinVar audit reports expert_panel_submissions=0 and identifies the available classifications as laboratory or other non-expert assertions.
• The ClinVar record used by the case is labeled NM_001048174.2:c.1103G>A (p.Gly368Asp), which does not match the assessed NM_001128425.2:c.1187G>A (p.Gly396Asp).

Sources

Reasoning

The governing InSiGHT/MUTYH framework is present but incomplete and provides no usable BA1 threshold, so the supplied generic ACMG/AMP threshold applies. The highest observed allele frequency is 0.00588456 in gnomAD v4.1 European (non-Finnish) individuals, with total AF 0.00473005; the non-cancer v2.1 exome AF is 0.00295109. All are below the generic BA1 stand-alone threshold of >=0.05 (ACMG/AMP 2015, PMID:25741868). Therefore BA1 is not met.

Rule

Generic ACMG/AMP BA1 stand-alone threshold >=0.05, used because the governing MUTYH framework is incomplete.

Evidence considered

• The InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification (version 1.0) is available, but its ruleset is incomplete and contains no usable BA1 threshold.
• gnomAD v4.1 reports total AF 0.00473005 and the highest population AF 0.00588456 in European (non-Finnish) individuals, with 26 total homozygotes.
• gnomAD v2.1 non-cancer exomes report AF 0.00295109 (695/235506 alleles; 3 homozygotes).
• The supplied generic ACMG/AMP BA1 threshold is >=0.05 (ACMG/AMP 2015, PMID:25741868); each observed frequency is below it.

Sources

Reasoning

The governing InSiGHT/MUTYH framework is present but incomplete and provides no usable BS1 threshold, so the supplied generic ACMG/AMP threshold applies. The highest observed allele frequency is 0.00588456 in gnomAD v4.1 European (non-Finnish) individuals, with total AF 0.00473005; the specified non-cancer v2.1 exome AF is 0.00295109. These values are below the generic BS1 threshold of >=0.01 (SVI default, with per-gene derivation preferred; Whiffin et al. 2017, PMID:28518168). Therefore BS1 is not met.

Rule

Generic ACMG/ClinGen-SVI BS1 threshold >=0.01, used because no usable MUTYH-specific rule is available.

Evidence considered

• The InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification (version 1.0) is available, but its ruleset is incomplete and contains no usable BS1 threshold.
• gnomAD v4.1 reports total AF 0.00473005 and the highest population AF 0.00588456 in European (non-Finnish) individuals.
• Because the case evidence identifies the non-cancer v2.1 exome subset, its exome-only AF 0.00295109 is also considered; it does not approach 0.01.
• The supplied generic BS1 threshold is >=0.01 (SVI default; Whiffin et al. 2017, PMID:28518168); the observed frequencies are below it.

Sources

Reasoning

BS3 is not met because validated functional studies do not show a normal or benign effect for p.G396D. In the exact-variant MutY-deficient E. coli complementation assay, p.G396D produced a 1.7-fold higher rifampicin-resistant mutation rate than wild-type MUTYH and was classified as partially defective using the study's prespecified cutoff. Additional reported human-cell and homologous MutY results show reduced substrate binding, reduced repair, an 86% reduction in adenine removal, and a six-fold slower removal rate. These damaging functional results are incompatible with applying a benign functional criterion.

Evidence considered

• The exact-variant complementation assay in PMID:25820570 used wild-type and empty-vector controls and classified p.G396D as partially defective at the study's 1.7-fold mutation-rate cutoff.
• PMID:19506731 reports reduced G396D substrate binding and repair in human cell lines and substantially reduced adenine removal in the corresponding E. coli MutY assay.
• Because the available biologically relevant assays show impaired rather than normal function, BS3 cannot be applied.

Sources

Reasoning

The variant is missense, so BP4 must be evaluated using REVEL only; SpliceAI is not applicable to this criterion for this consequence. REVEL is 0.954, which is above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997), so BP4 is not met. The MUTYH VCEP framework was reviewed first but contains no applicable PP3/BP4-specific rule.

Rule

Missense REVEL: BP4 supporting at <=0.29; use REVEL only and do not use SpliceAI for this missense consequence.

Evidence considered

• The variant consequence is missense, p.Gly396Asp; therefore REVEL is the sole applicable computational path for PP3/BP4.
• Local REVEL lookup reports a score of 0.954.
• ClinGen SVI REVEL calibration specifies supporting BP4 at <=0.29 (Pejaver et al. 2022, PMID:36413997).
• The MUTYH VCEP framework was reviewed first; its available rule payload contains no applicable PP3/BP4-specific assignment, so the supplied generic calibration was used.

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The ClinVar audit reports zero expert-panel submissions and no qualifying benign or likely-benign expert-panel assertion. Laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger BP6.

Rule

BP6 requires an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• The ClinVar audit reports expert_panel_submissions=0 and contains no qualifying exact-variant benign or likely-benign expert-panel classification.
• The available ClinVar classifications are pathogenic or likely pathogenic laboratory assertions, which cannot trigger BP6 under the specified rule.

Sources

Reasoning

The variant is NP_001121897.1:p.Gly396Asp (c.1187G>A), but the reviewed evidence does not establish an independently occurring pathogenic nucleotide change that produces the same amino-acid substitution. The available exact-variant papers study this same nucleotide/protein change rather than a distinct codon change, and the PM5 candidate collection contains no comparators. Because absence from the available evidence is not proof that no same-amino-acid comparator exists, PS1 cannot be assessed.

Rule

Generic PS1 requires a different pathogenic nucleotide change resulting in the same amino-acid change; no such comparator was established here.

Evidence considered

• PMID:19506731 explicitly discusses MUTYH p.G396D, but it evaluates the exact G396D variant and does not provide a distinct nucleotide change encoding the same amino-acid substitution.
• PMID:25820570 functionally studies the exact p.G396D variant and likewise does not establish a distinct same-amino-acid pathogenic comparator.
• The available PM5 comparator record contains zero collected candidates, so it does not resolve whether a qualifying PS1 comparator exists.

Still missing

• A comprehensive search for independent pathogenic variants producing the same p.Gly396Asp amino-acid change is still required.

Sources

Reasoning

PS2 cannot be assessed because the available case evidence contains no documented proband-parent genotypes, confirmed de novo status, parental relationship testing, or exclusion of parental mosaicism for NM_001128425.2:c.1187G>A (p.Gly396Asp). The retrieved MUTYH InSiGHT framework is present but unstructured and provides no criterion-specific PS2 rule. The available exact-variant publications address functional effects and population observations, not a confirmed de novo occurrence.

Rule

No criterion-specific MUTYH rule was available in the retrieved InSiGHT ruleset; generic ACMG/AMP PS2 definition used only to identify the missing de novo evidence.

Evidence considered

• The available case evidence does not document parental testing, parent-child genotypes, or a confirmed de novo event.
• The MUTYH InSiGHT framework is identified, but its retrieved ruleset is unstructured and contains no PS2-specific rule.
• The exact-variant publications reviewed report functional or population findings rather than a confirmed de novo occurrence.

Still missing

• Proband and both parental variant genotypes are not documented.
• Parental relationship and de novo confirmation are not documented.
• Parental mosaicism assessment is not documented.

Sources

Reasoning

PS4 requires case-control enrichment or sufficient affected-case evidence for the exact variant. The available reported odds ratio of 6.87 with p<0.0005 concerns NM_001048174.2:c.1103G>A (p.Gly368Asp), not the assessed NM_001128425.2:c.1187G>A (p.Gly396Asp), and therefore cannot be transferred. Papers mentioning p.G396D describe its occurrence in MUTYH-associated polyposis or functional studies but do not provide an exact-variant case-control enrichment result sufficient for PS4. No numeric PS4 comparison is applicable.

Rule

Assess only exact-variant case-control enrichment or qualifying affected-case evidence; no applicable exact-variant numeric PS4 threshold comparison is available.

Evidence considered

• The case materials report an odds ratio of 6.87 with p<0.0005 for c.1103G>A, but that is a different MUTYH variant from the assessed c.1187G>A/p.Gly396Asp.
• PMID:19506731 discusses p.G396D in functional and population context but does not provide an exact-variant case-control enrichment estimate for this assessment.
• PMID:25820570 reports p.G396D among common variants in Caucasian patients with MUTYH-associated polyposis, but does not establish an exact-variant PS4 case-control threshold comparison.

Still missing

• Exact-variant case-control counts or an exact-variant odds ratio with a governing PS4 threshold are unavailable.
• The ClinVar-linked variant identity conflicts with the assessed HGVS, mapping to c.1103G>A/p.Gly368Asp rather than c.1187G>A/p.Gly396Asp.

Sources

Reasoning

The governing InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive but provides no structured PM3 rule. Generic PM3 therefore requires an affected individual with the variant observed in trans with a pathogenic or likely pathogenic MUTYH variant, with phase established or otherwise sufficiently supported. PMID:19506731 discusses human cell lines with biallelic G396D mutations, but the extracted evidence does not identify affected probands, a second pathogenic or likely pathogenic allele, or cis/trans phase for the case variant. PM3 cannot be applied from this evidence.

Rule

For an autosomal-recessive disorder, apply PM3 only when the variant is observed in trans with a pathogenic or likely pathogenic allele in an affected individual; phase and phenotype must be documented sufficiently.

Evidence considered

• The governing InSiGHT specification identifies MUTYH-related familial adenomatous polyposis 2 as autosomal recessive, but its retrieved rule payload contains no structured PM3 instruction.
• Generic PM3 requires disease-relevant affected-proband evidence showing the tested variant in trans with a pathogenic or likely pathogenic allele in a recessive disorder.
• PMID:19506731 reports human cell lines with biallelic G396D mutations and functional impairment, but does not provide the affected-proband, second-allele, and phase details required for PM3.

Still missing

• An affected-proband observation carrying NM_001128425.2:c.1187G>A is needed.
• A second pathogenic or likely pathogenic MUTYH variant and validated cis/trans phase are not documented.

Sources

Reasoning

PM5 requires a different pathogenic missense change at the same residue. The available evidence establishes functional findings for p.Gly396Asp itself, but does not document a distinct pathogenic missense substitution at residue 396. The collected PM5 artifact reports zero same-residue candidates and explicitly cannot confirm classic PM5 semantics; therefore PM5 is not assessed rather than called absent.

Rule

Generic PM5 requires an independently established pathogenic missense variant at the same amino-acid residue; this was not established from the available evidence.

Evidence considered

• The governing MUTYH framework is available but unstructured and does not provide a usable PM5-specific rule.
• The collected PM5 candidate record reports zero same-residue candidates and states that classic PM5 semantics could not be confirmed safely.
• The reviewed exact-variant papers concern p.G396D itself and do not establish a different pathogenic missense substitution at residue 396.

Still missing

• A complete same-residue ClinVar and literature review is needed to determine whether another pathogenic missense variant at Gly396 qualifies for PM5.

Sources

Reasoning

PM6 cannot be assessed because the available case evidence contains no report of NM_001128425.2:c.1187G>A (p.Gly396Asp) arising de novo without parental testing. No proband phenotype-linked case report with an unconfirmed but plausible de novo event is documented. The retrieved MUTYH InSiGHT framework is present but unstructured and provides no criterion-specific PM6 rule.

Rule

No criterion-specific MUTYH rule was available in the retrieved InSiGHT ruleset; generic ACMG/AMP PM6 definition used only to identify the missing de novo evidence.

Evidence considered

• The available case evidence does not report a suspected de novo occurrence of the variant.
• The MUTYH InSiGHT framework is identified, but its retrieved ruleset is unstructured and contains no PM6-specific rule.
• The exact-variant publications reviewed concern functional or population findings and do not document a de novo clinical case.

Still missing

• No case report documents this variant as a suspected de novo event.
• No parental testing or family-history information is available to support an unconfirmed de novo interpretation.

Sources

Reasoning

PP1 cannot be assessed because the available evidence does not provide affected or unaffected relatives, variant genotypes, phenotype status, or informative meioses for NM_001128425.2:c.1187G>A (p.Gly396Asp). The exact-variant publications reviewed describe functional studies and population observations, but do not provide segregation data for this variant. The retrieved MUTYH InSiGHT framework is present but unstructured and provides no criterion-specific PP1 rule.

Rule

No criterion-specific MUTYH rule was available in the retrieved InSiGHT ruleset; generic ACMG/AMP PP1 definition used only to identify the missing segregation evidence.

Evidence considered

• The available case evidence contains no family segregation table or informative meiosis count for the variant.
• The exact-variant publications reviewed report functional findings for p.G396D but no affected-relative segregation analysis.
• The MUTYH InSiGHT framework is identified, but its retrieved ruleset is unstructured and contains no PP1-specific rule.

Still missing

• No affected-relative genotypes and phenotypes are documented.
• No unaffected-relative genotypes are documented.
• No informative meioses or segregation count is available.
• No family-level clinical diagnosis and variant phase information are available.

Sources

Reasoning

The available MUTYH framework does not expose a PP2-specific rule, and the reviewed evidence does not provide a validated gene-level quantitative assessment showing that missense variation is an unusually common pathogenic mechanism with a low benign missense rate. Exact-variant functional results cannot substitute for the gene-level PP2 prerequisite.

Rule

PP2 requires gene-level evidence that missense variants are a common pathogenic mechanism and benign missense variation is uncommon; that prerequisite was not established.

Evidence considered

• The governing MUTYH framework is present but unstructured and does not provide a PP2 rule or gene-specific missense metric.
• The exact p.G396D functional studies address this variant's effect, not the gene-level frequency or mechanism requirement for PP2.

Still missing

• A gene-level missense constraint or validated pathogenic-versus-benign missense distribution supporting PP2 is required.

Sources

Reasoning

PP4 requires a highly specific phenotype or phenotype pattern in the evaluated patient or family. The available evidence associates p.G396D with MUTYH-associated polyposis and describes functional consequences, but the case materials do not provide the patient's phenotype, family history, or a phenotype-specific diagnostic pattern. Gene-disease association and variant occurrence in affected cohorts alone are insufficient to apply PP4.

Rule

Apply PP4 only when the patient's phenotype or family history is highly specific for the relevant disease; do not infer it from gene-level disease association alone.

Evidence considered

• PMID:19506731 states that p.G396D occurs in MUTYH-associated polyposis and describes defective MUTYH activity, but it does not supply the phenotype of the present case.
• PMID:25820570 reports p.G396D in patients with MUTYH-associated polyposis, but cohort association is not a substitute for a highly specific phenotype documented for this patient.

Still missing

• Patient phenotype and relevant family history are not documented in the available evidence.
• A highly specific phenotype pattern linked to this patient's exact variant is not established.

Sources

Reasoning

gnomAD reports homozygous observations, including 26 in v4.1 and 3 in the non-cancer v2.1 exome subset, but these population records do not establish that the individuals were clinically unaffected, sufficiently aged for MUTYH-associated polyposis/colorectal cancer assessment, or phenotyped with adequate penetrance information. Consequently, the available homozygote counts cannot validly establish BS2, which requires observation in an appropriately unaffected individual or individuals.

Rule

BS2 requires appropriately unaffected individuals; population homozygote counts without phenotype, age, and penetrance ascertainment are insufficient.

Evidence considered

• gnomAD v4.1 reports 26 homozygotes overall, including 25 in European (non-Finnish) individuals.
• gnomAD v2.1 non-cancer exomes report 3 homozygotes, and gnomAD v3.1 non-cancer reports 1 homozygote.
• Non-cancer cohort membership is not equivalent to a documented unaffected phenotype or adequate age-based exclusion of a recessive, variably penetrant condition; therefore these counts are insufficient to apply BS2.

Still missing

• Clinical phenotype, age, cancer history, and ascertainment data for the reported homozygous individuals are unavailable.
• No verified evidence establishes that these homozygotes are unaffected despite adequate age and penetrance for MUTYH-associated polyposis or colorectal cancer.

Sources

Reasoning

BS4 cannot be assessed because the available evidence does not document an unaffected relative who was tested and carried NM_001128425.2:c.1187G>A (p.Gly396Asp), nor does it provide a family phenotype and genotype dataset demonstrating non-segregation. Population frequency and functional findings do not establish family non-segregation. The retrieved MUTYH InSiGHT framework is present but unstructured and provides no criterion-specific BS4 rule.

Rule

No criterion-specific MUTYH rule was available in the retrieved InSiGHT ruleset; generic ACMG/AMP BS4 definition used only to identify the missing non-segregation evidence.

Evidence considered

• The available case evidence contains no tested unaffected-relative result or family-level non-segregation analysis.
• Population frequency and functional observations cannot substitute for documented family non-segregation.
• The MUTYH InSiGHT framework is identified, but its retrieved ruleset is unstructured and contains no BS4-specific rule.

Still missing

• No unaffected relatives with documented variant testing are identified.
• No family genotype-phenotype table is available.
• No non-segregation analysis or penetrance-adjusted interpretation is available.

Sources

Reasoning

The available MUTYH framework does not expose a BP1-specific rule, and the reviewed evidence does not provide a validated gene-level estimate demonstrating that disease-causing variants are predominantly truncating with a low missense contribution. The existence of functional studies for p.G396D alone cannot resolve this gene-level criterion.

Rule

BP1 requires a gene in which pathogenic variants are known to be predominantly truncating and missense variants are not a typical disease mechanism; this was not established.

Evidence considered

• The governing MUTYH framework is present but unstructured and supplies no BP1 rule or quantitative variant-spectrum threshold.
• The reviewed publications describe MUTYH disease and exact-variant functional findings but do not establish the gene-level predominance requirement for BP1.

Still missing

• A validated MUTYH variant-spectrum analysis or gene-specific rule supporting BP1 is required.

Sources

Reasoning

The governing InSiGHT MUTYH specification identifies familial adenomatous polyposis 2 as autosomal recessive but provides no structured BP2 rule. Under the generic ACMG definition, BP2 for a recessive disorder requires the variant to be observed in cis with a pathogenic or likely pathogenic variant, or another clearly qualifying allelic configuration under an applicable specification. The available evidence does not document a second pathogenic or likely pathogenic MUTYH variant in the same individual, nor cis phase. BP2 cannot be applied or excluded.

Rule

For a recessive disorder, apply BP2 only when the variant is documented in cis with another pathogenic or likely pathogenic allele, or when an applicable gene-specific rule defines an equivalent qualifying configuration.

Evidence considered

• The governing InSiGHT specification identifies the relevant MUTYH disease as autosomal recessive, but its retrieved rule payload contains no structured BP2 instruction.
• Generic BP2 for a recessive disorder requires documented cis occurrence with another pathogenic or likely pathogenic variant; no such same-individual co-occurrence or phase evidence is available here.

Still missing

• A same-individual observation with a second pathogenic or likely pathogenic MUTYH variant is not documented.
• Validated cis phase, or another qualifying BP2 configuration under a specific MUTYH rule, is not documented.

Sources

Reasoning

No applicable MUTYH-specific BP5 rule or qualifying evidence of an alternative molecular explanation for the relevant phenotype is available. The materials contain disease-associated and functional information for MUTYH variants, but do not document an alternative pathogenic variant or other molecular cause that would satisfy BP5 for this case. No numeric BP5 comparison is applicable.

Rule

Assess BP5 only with a documented qualifying alternative molecular explanation under an applicable specification; no numeric threshold is applicable here.

Evidence considered

• The retrieved MUTYH framework is an incomplete unstructured ruleset and provides no usable BP5 rule for this assessment.
• The available case evidence does not identify an alternative pathogenic variant or independent molecular diagnosis that could satisfy BP5.

Still missing

• An alternative molecular explanation for the relevant phenotype is not documented.
• No applicable MUTYH-specific BP5 specification is available in the retrieved framework.

Sources