MUTYH c.1476+2C>T, p.?

Reasoning

PP3 (computational evidence of a deleterious effect; Richards et al. 2015, PMID:25741868) was evaluated on the splice-prediction path, because NM_001128425.2:c.1476+2C>T in MUTYH is an intronic splice-region change at the canonical splice-donor +2 position (MANE Plus Clinical transcript NM_001128425.2, minus strand), not a missense substitution; the missense path (REVEL) therefore does not apply and was not consulted. SpliceAI (spliceailookup.broadinstitute.org, hg19, Gencode basic, max distance 500, no masking) returns a maximum delta score of 0.257, contributed by donor loss (DS_DL = 0.257; other channels DS_AG 0.049, DS_AL 0.001, DS_DG 0.084 with delta positions DP_AG 127, DP_AL -263, DP_DG 2, DP_DL 64); Pangolin SG 0.438, SL -0.081, and the lookup annotates the change as a splice donor variant. Under the calibrated SpliceAI thresholds (supporting >= 0.2, moderate >= 0.5; Jaganathan et al. 2019, Cell, PMID:30661751), a delta of 0.257 meets PP3 at supporting strength only, falling short of the 0.5 moderate cutoff. The governing ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for MUTYH v1.0 (CSPEC doc 1742141534) was located and checked first, but the retrieved specification content contains no PP3/BP4 threshold and no pre-assigned computational code for this variant, and no gene-specific PP3/BP4 lookup table was present, so the generic ClinGen SVI splice calibration was applied. Two caveats are flagged for review rather than used to alter the call: the predicted donor-loss delta is lower than is typical for a canonical +2 change and its delta position (64 nt from the variant) is not the canonical donor itself, so the SpliceAI call is worth verifying; and the same donor-loss prediction underlies the canonical splice disruption that the consequence/LOF arm may count under PVS1, so PP3 should not be double-weighted against that evidence in the final combination.

Rule

SpliceAI max delta >= 0.2 -> PP3 supporting (Jaganathan et al. 2019, Cell, PMID:30661751); >= 0.5 would be moderate.

Evidence considered

• SpliceAI lookup for NM_001128425.2:c.1476+2C>T / chr1:45796852 G>A (hg19): max delta score 0.257, from donor loss (DS_DL 0.257; DS_AG 0.049, DS_AL 0.001, DS_DG 0.084; DP_AG 127, DP_AL -263, DP_DG 2, DP_DL 64), Pangolin SG 0.438 / SL -0.081; the lookup result annotates the change as a splice donor variant on MANE Plus Clinical transcript NM_001128425.2 (minus strand).
• SpliceAI online lookup screenshot (spliceailookup.broadinstitute.org, hg19, Gencode basic, max distance 500) shows the scores table with Donor Loss 0.26 and Acceptor Loss 0.05, and lists NM_001128425.2 (MANE Plus Clinical) and NM_001048174.2 (MANE Select) both as protein-coding splice donor variants.
• Path selection: the variant is intronic/splice-region (canonical splice donor +2), so PP3/BP4 take evidence from the SpliceAI path only; REVEL returned no score for this position and the available BayesDel value (-0.0838218) was not used, since BayesDel has no established published ACMG-strength calibration for PP3/BP4 and is a missense-path predictor.
• Thresholds applied verbatim: SpliceAI PP3 supporting >= 0.2 and moderate >= 0.5 (Jaganathan et al. 2019, Cell, PMID:30661751); BP4 supporting <= 0.1.
• Governing-framework check: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for MUTYH v1.0 (CSPEC doc 1742141534, NM_001128425.2/NM_001048174.2, familial adenomatous polyposis 2, autosomal recessive) retrieved; its criteria list and rule payload are empty, and the CSPEC display page contains no PP3/BP4 rule text, so no pre-assigned code could be taken from it.
• Full-text/finding extracts available for this case (PMID:25186627, 25356965, 25394175, 25452455, 25645574, 25741868, 26467025) were checked for in-silico or splice-prediction content relevant to PP3/BP4; all are cohort, guideline, or framework documents with no SpliceAI/REVEL calibration or variant-specific predictor data, so none was used to support or refute this criterion.

Still missing

• No VCEP-specific PP3 threshold or pre-assigned computational code is retrievable for MUTYH: the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP MUTYH v1.0 specification is present but yields no criteria text or PP3/BP4 rule, so generic ClinGen SVI SpliceAI calibration governs this call.
• SpliceAI donor-loss delta for a canonical +2 change is atypically low (0.257, delta position 64 nt from the variant rather than at the canonical donor); the prediction should be confirmed (e.g. against the lookup table or an orthogonal splice predictor) before final weighting.

Sources

Reasoning

PVS1 requires a null (truncating) allele: a nonsense/frameshift/canonical +/-1,2 splice or initiation-codon variant that abolishes protein function, evaluated through the ClinGen SVI PVS1 decision tree (pvs1_generic_framework, PMC6185798). The governing specification was checked first: the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for MUTYH v1.0 (CSPEC doc 1742141534) is registered for this case and MUTYH loss of function is the established recessive mechanism (biallelic LoF causes MUTYH-associated polyposis, familial adenomatous polyposis 2), but the retrieved CSPEC content carries an empty criteria list and empty rule payload, so no VCEP-specific PVS1 rule or pre-assigned code exists and the generic SVI PVS1 framework governs. NM_001128425.2:c.1476+2C>T (GRCh38 chr1:g.45331180G>A) sits at the +2 position of the intron 14 donor of the ClinGen-preferred/MANE Plus Clinical transcript NM_001128425.2, i.e. the last base of exon 14 (c.1476) is joined to a donor dinucleotide that is non-canonical. Reading the transcript against the GRCh38 reference sequence on the MUTYH minus strand, exon 14 spans c.1324_1476 (153 nt, confirmed by aligning the RefSeq NM_001128425.2 exon annotation to the genomic reference) and the donor at c.1476+1/+2 is GC; the c.1476+2C>T change converts that GC donor to GT, the canonical/consensus donor. The variant is therefore predicted to strengthen, not abolish, the native donor, so the first PVS1 gate (a variant type predicted to cause a null effect) is not satisfied. Independently, even under the maximal-effect assumption that the donor is lost and exon 14 is skipped entirely, the consequence is NOT a null allele: exon 14 is 153 nt, exactly 51 codons, so joining exon 13 to exon 15 is in-frame, deleting codons 442-492 (51 of 550 residues, 9.3% of NP_001121897.1) with no downstream frameshift, no premature termination codon and therefore no NMD - the exon-14 skip removes only the C-terminal portion of the exon and leaves the rest of the reading frame and the natural stop codon intact. An in-frame deletion does not meet PVS1 even at reduced strength; per the ACMG/AMP 2015 framework, in-frame length changes that may retain critical protein domains are handled by PM4-type reasoning, not PVS1 (PMID:25741868); the same principle appears in the rules-based scoring framework, where canonical +/-1,2 changes are treated as null only when the event is out-of-frame and disease-relevant LoF is documented, with explicit exceptions for variants escaping NMD or falling in a non-relevant isoform (PMID:26467025). Functional prediction is concordant and does not indicate a catastrophic splice effect: SpliceAI (hg19 lookup, Gencode basic, distance 500) returns a maximum delta of 0.257, attributed to donor loss (DS_DL 0.257; DS_AG 0.049, DS_AL 0.001, DS_DG 0.084; DP_DG 2, DP_DL 64), which is far below the 0.5 delta expected for a genuinely abolished donor and below the 0.5 moderate in-silico threshold; the affected delta position is not the native donor itself, which is consistent with the donor being retained/strengthened. Independent submitter evidence points the same way: in ClinVar (variation 187040; NM_001048174.2:c.1392+2C>T and NM_001128425.2:c.1476+2C>T are the same genomic change) several clinical laboratories state that the change alters a non-canonical donor site into a consensus GT donor and that no significant impact on normal splicing is predicted. Because no null effect is predicted on either the donor-strengthening analysis or the in-frame exon-14 arithmetic, PVS1 is not met and no strength tier is assigned; writing any strength here would misrepresent a variant whose maximal predicted consequence is an in-frame 51-residue deletion rather than a truncated protein. The one genuine gap is empirical: no RNA/cDNA or minigene data establish the actual transcript outcome, so the conclusion rests on reference-annotation and prediction rather than assay, which is why this call is flagged for human review.

Rule

ClinGen SVI PVS1 decision tree (PMC6185798), applied generically because the InSiGHT MUTYH v1.0 CSPEC contains no PVS1 rule: PVS1 is only met when the variant is predicted to cause a null effect (NMD-triggering PTC, or a canonical splice variant that abolishes the site). NM_001128425.2:c.1476+2C>T fails this gate on two independent grounds: the native intron 14 donor is non-canonical GC and the change makes it the consensus GT donor (strengthening, not abolishing, the site), and the maximal predicted consequence - complete exon 14 skipping - is in-frame (153 nt = 51 codons, no PTC, no NMD). Result: PVS1 not met, strength null (no very strong/strong/moderate/supporting tier assigned, because no null effect is predicted and no SVI/VCEP downgrade rule is invoked).

Evidence considered

• Framework precedence: the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for MUTYH v1.0 (CSPEC doc 1742141534, URL cspec.genome.network/cspec/ui/svi/doc/1742141534) is present for this case with preferred transcripts NM_001128425.2 and NM_001048174.2 and mode of inheritance autosomal recessive (familial adenomatous polyposis 2, MONDO:0012041), but its criteria array and rule payload are empty, so no VCEP-specific PVS1 specification and no pre-assigned criterion code were available; the generic ClinGen SVI PVS1 recommendations (PMC6185798) were therefore applied.
• Variant identity and consequence class: NM_001128425.2:c.1476+2C>T (NP_001121897.1:p.?) on MANE Plus Clinical transcript NM_001128425.2, GRCh37 NC_000001.10:g.45796852G>A / GRCh38 NC_000001.11:g.45331180G>A, MUTYH minus strand; VariantValidator places the change in the intron adjacent to exon 14 ('14i'), i.e. the +2 position of the exon 14 splice donor.
• Gene-level eligibility for a PVS1 assessment: MUTYH germline loss of function is an established disease mechanism for MUTYH-associated polyposis (autosomal recessive, biallelic LoF), so the SVI PVS1 gene-mechanism gate is passed and MUTYH is eligible for PVS1 evaluation; the PVS1 gene gate was recorded as 'eligible'.
• Exon/reading-frame arithmetic (reference-sequence derivation): the RefSeq GenBank record for NM_001128425.2 annotates 16 exons with CDS 187..1836, so exon 14 is mRNA 1510..1662 = c.1324_1476 (153 nt) and exon 15 is mRNA 1663..1704 = c.1477_1518 (42 nt); reverse-complementing GRCh38 chr1:45,331,182-45,331,334 reproduces mRNA 1510..1662 exactly, confirming the exon 14 boundaries. Exon 14 is therefore exactly 51 codons and starts exactly at a codon boundary (1323 coding bases upstream = 441 codons), so skipping exon 14 joins exon 13 to exon 15 in frame, deleting codons 442-492 (51 of 550 residues) with no frameshift and no premature termination codon -> no NMD and no truncated product.
• Donor-sequence analysis (reference-sequence derivation): the native exon 14 donor dinucleotide at c.1476+1/+2 reads GC in transcript orientation (genomic plus-strand chr1:45,331,181 C and chr1:45,331,180 G on the minus-strand transcript); c.1476+2C>T changes the +2 base C to T, converting this non-canonical GC donor into the canonical GT (consensus) donor. The variant is thus predicted to strengthen rather than disrupt the donor, so the variant-type gate of the SVI PVS1 decision tree (a change predicted to cause a null effect) is not satisfied and no truncation/NMD branch is reached.
• SpliceAI lookup (spliceailookup.broadinstitute.org, transcript NM_001128425.2, hg19, Gencode basic, distance 500, masking off): maximum delta score 0.257, contributed by donor loss (DS_DL 0.257; DS_AG 0.049, DS_AL 0.001, DS_DG 0.084 with delta positions DP_AG 127, DP_AL -263, DP_DG 2, DP_DL 64); Pangolin SG 0.438 / SL -0.081, and the lookup annotates the change as a splice donor variant. A donor-loss delta of 0.257 is well below the 0.5 delta expected when a donor is genuinely abolished (and below the published >=0.5 moderate splice-prediction threshold, Jaganathan et al. 2019, Cell, PMID:30661751), so the predictor supplies no support for complete loss of the native donor; the donor-loss delta position is not the native donor itself.
• ClinVar (variation 187040, NM_001048174.2(MUTYH):c.1392+2C>T / NM_001128425.2:c.1476+2C>T, same genomic change chr1:45,331,180G>A): record is 'Conflicting classifications of pathogenicity' (last evaluated 2026-01-31) with the submitter mix recorded for this case as 10 Uncertain significance, 2 Benign, 2 Likely benign and 1 Likely pathogenic, and ClinVar annotates the molecular consequence as 'splice donor variant'. Submitter commentary recorded for this record states the change is predicted to affect mRNA splicing on the one hand, but also that the variant 'restores'/'changes a non-classical splice site into a classic, consensus splice site' and that no significant impact on normal splicing is expected (Women's Health and Genetics/LabCorp: '4/4 computational tools predict that this variant strengthens the canonical 5' splicing donor site (i.e. it seems to change a non-classical splice site into a classic, consensus splice site), therefore no significant impact on normal splicing is expected'; PreventionGenetics: 'This variant is predicted to restore the donor splice site in intron 14 to a consensus splice site (GT) based on available splicing prediction programs'). These statements were used only as corroboration of the reference-sequence finding that the native donor is a non-canonical GC that this change makes canonical; the ClinVar aggregate classification was not used to infer this criterion.
• ACMG/AMP 2015 framework (PMID:25741868), PVS1 section: canonical +/-1,2 splice-site variants are among the types that 'can often be assumed to disrupt gene function', but the actual impact of a splice variant (exon skipping, shortening, or inclusion of intronic material) is only predicted and requires functional RNA/protein confirmation; the same document notes that an in-frame deletion/insertion may retain critical protein domains and produce a mild or neutral effect, handled outside PVS1. Applied here: the maximal predicted consequence of this variant is an in-frame 51-residue deletion with no PTC, not a null allele.
• Rules-based weighted scoring methodology (PMID:26467025): canonical +/-1,2 splice-site variants associated with out-of-frame events were assigned null-variant weight only in genes where such null variants are documented to cause well-characterised disease, with explicit exceptions for variants escaping NMD, variants in a non-relevant isoform, and poorly characterised mechanisms. No MUTYH- or variant-specific data are reported there; the source was consulted only for the out-of-frame requirement underpinning the not-met call for this in-frame outcome.
• Paper extracts and available full texts for this case (PMID:25186627, 25356965, 25394175, 25452455, 25645574, 25741868, 26467025) were checked for this exact variant: no source reports c.1476+2C>T (or the equivalent c.1392+2C>T) or any transcript/functional data on it, so no literature evidence establishes a null effect for this variant.

Still missing

• No RNA/cDNA (RT-PCR), long-read or minigene assay data are available for this variant, so the actual transcript consequence (exon 14 skipping versus normal splicing) is predicted, not experimentally demonstrated; direct RNA evidence would be the definitive confirmation of this not-met call.
• The ClinGen InSiGHT MUTYH v1.0 CSPEC is registered for this case but was retrieved with an empty criteria list and empty rule payload, so no VCEP-specific PVS1 rule, splice-variant decision branch or pre-assigned code could be applied; the generic ClinGen SVI PVS1 framework was used instead, and a published VCEP PVS1 rule would need this call re-run against it.
• InSiGHT/VCEP splice-variant handling for MUTYH (if any) could not be verified: no gene-specific PVS1 splice decision tree or exon-importance table was present in the case materials.

Sources

Reasoning

PS3 requires well-established functional studies - with adequate assay controls and biological relevance to the gene-disease mechanism - demonstrating a damaging effect on protein function or splicing (Richards et al. 2015, PMID:25741868). The governing gene-specific specification for MUTYH is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification V1.0 (cspec), which was retrieved for this case but returned as an unstructured ruleset with an empty criteria payload (framework_complete=false, rule_payload={}), so no gene-specific PS3 rule exists and the generic ACMG/AMP 2015 definition applies. NM_001128425.2:c.1476+2C>T (NC_000001.10:g.45796852G>A, NP_001121897.1:p.?) is a canonical donor +2 change. No functional assay of this variant - RNA-based splicing analysis (patient RNA or minigene reporter) or a MUTYH glycosylase-activity assay - was found in any source examined. Literature triage indexed two papers as PS3 leads: PMID:26467025, a rules-based weighted pathogenicity-scoring methodology applied to 338 non-MUTYH genes that neither names MUTYH nor this variant, and PMID:33471991, a breast-cancer risk association study that was not retrieved as full text and is a case-control design rather than a functional assay. The six other full texts available for this case (PMID:25186627, PMID:25356965, PMID:25394175, PMID:25452455, PMID:25645574, PMID:25741868) contain no functional assay data for MUTYH c.1476+2C>T, and the exact variant does not appear in any of them. ClinVar submitters independently document the same absence: SCV000697679 (LabCorp), whose submission carries a PS3 annotation, states of this variant that '...these predictions have yet to be confirmed by functional studies', and SCV004817134 (All of Us Research Program) states 'to our knowledge, functional studies have not been reported for this variant'. The only variant-specific molecular data are computational (SpliceAI max delta 0.257, DS_DL 0.257; Pangolin SG 0.438), which predict partial donor-site loss but are not a functional measurement and cannot substitute for an assay. No assay controls, no calibrated likelihood ratio and no assay validation data exist for this variant, so PS3 strength calibration cannot be performed. PS3 is therefore not met on absence of evidence. The ClinVar classification of this variant was not used to infer this criterion.

Rule

ACMG/AMP 2015 PS3 (Richards et al., PMID:25741868): requires well-established functional studies showing a damaging effect; no gene-specific PS3 rule in the InSiGHT MUTYH CSPEC V1.0 ruleset as retrieved (unstructured, empty criteria payload)

Evidence considered

• Governing framework: the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification to the ACMG/AMP guidelines for MUTYH V1.0 (cspec) is the applicable gene-specific specification, but it was returned unstructured with an empty criteria payload, so the generic ACMG/AMP 2015 PS3 definition (Richards et al., PMID:25741868) was applied.
• PMID:25741868 (ACMG/AMP 2015) defines PS3 as evidence from well-established functional studies showing a damaging effect, and explicitly states for splice-site variants that 'confirmation of impact requires functional analysis by either RNA or protein analysis' - i.e. the computational prediction for a canonical +2 change such as c.1476+2C>T is not itself PS3 evidence.
• ClinVar VCV000187040 carries a PS3-coded submission: SCV000697679 (Women's Health and Genetics/LabCorp) recorded that 4/4 computational tools predict the variant strengthens the canonical 5' splicing donor site but that '...however, these predictions have yet to be confirmed by functional studies'; the submission therefore documents absence of functional evidence rather than presence of it.
• SCV004817134 (All of Us Research Program, NIH) records for this variant: 'to our knowledge, functional studies have not been reported for this variant'.
• The only variant-specific molecular data are computational: SpliceAI max delta 0.257 (DS_DL 0.257, DS_AG 0.049, DS_AL 0.001, DS_DG 0.084; Pangolin SG 0.438, SL -0.081) - a prediction of partial donor-site loss, not a functional measurement.
• PMID:26467025 (indexed by literature triage as a PS3 lead) is a methodology paper on a rules-based weighted pathogenicity score applied to 16,500 assessments across 338 genes for neurological, endocrine and nephrotic disorders; it contains no MUTYH data and does not mention c.1476+2C>T, so it provides no functional evidence for this variant.
• PMID:25186627 (25-gene panel in 2,158 breast cancer patients) reports biallelic MUTYH mutations in 2 patients and monoallelic MUTYH mutations in 42, but names no specific MUTYH variant and performs no functional assay, so it cannot support PS3.
• No somatic or functional-assay database yielded variant-level functional data: COSMIC returned no result for MUTYH c.1476+2C>T, and the OncoKB page failed to load; neither is a functional assay source in any case.
• Absence of any assay means there is no experimental_context with controls, no orthogonal validation and no likelihood ratio, so PS3 strength calibration (supporting/moderate/strong) could not be derived from this evidence.
• The ClinVar aggregate classification (Conflicting classifications of pathogenicity) was not used to infer this criterion.

Still missing

• No functional assay of MUTYH c.1476+2C>T has been reported: no RNA-based splicing analysis (patient-derived RNA or minigene reporter) and no MUTYH glycosylase-activity assay, so PS3 cannot be met.
• No assay validation data (controls, replicates, orthogonal confirmation) or calibrated likelihood ratio exist for this variant; PS3 strength calibration is therefore not applicable.
• PMID:33471991 is indexed as a PS3 lead by literature triage but its full text was not retrieved for this case, so its PS3 relevance could not be inspected directly; its title and design indicate a case-control risk-association study rather than a functional assay.

Sources

Reasoning

PS4 (Richards et al. 2015, PMID:25741868) requires that the prevalence of the variant in affected individuals be significantly increased compared with its prevalence in controls. No case-control, case-cohort, or enrichment study reports MUTYH NM_001128425.2:c.1476+2C>T. The variant string (and its alternate-transcript equivalent c.1392+2C>T, NM_001048174.2) occurs zero times in every full text retrieved for this case, including the only retrieved cohort study of MUTYH carriers in a testing population (Tung et al. 2015, PMID:25186627: 2158 breast-cancer probands, 2 biallelic MUTYH carriers, no individual MUTYH variant named) and the practice guidelines and methodology papers that ClinVar cites for the record (PMID:25394175, PMID:25452455, PMID:25645574, PMID:25741868, PMID:26467025, PMID:25356965) - all of which are gene-level or framework documents with no variant-level case data. The ClinVar record (VCV 187040 / ClinVarID 187040) is an aggregate of 17 laboratory submissions with no case-control structure and no proband/control counts usable for enrichment (10 Uncertain significance, 2 Benign, 2 Likely benign, 1 Likely pathogenic, 1 additional Uncertain significance); aggregate submission counts are not case-control data, and the record contains no expert-panel assessment. In the control direction the variant is not rare-absent: it is present in gnomAD v4.1 at 131/1,614,160 alleles (AF 8.12e-05) and in gnomAD v2.1 at 37/282,888 alleles (AF 1.31e-04), with maximum population AF 0.00128 (African/African American); with zero documented affected carriers there is no case arm against which any enrichment could be measured, so the enrichment the criterion demands is refuted in direction as well as absent in data. No numeric threshold was applied for PS4 and no inequality was evaluated: the governing ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for MUTYH v1.0 (CSpec doc 1742141534) exists in name only for this case - it exposes no criteria codes (its rules are listed as in prep) - and generic ACMG/AMP PS4 defines no numeric odds-ratio or likelihood-ratio cutoff, so no operator (>= or <=) could be quoted for this criterion and none was used.

Rule

generic ACMG/AMP 2015 PS4 (Richards et al. 2015, PMID:25741868): prevalence in affected individuals significantly increased vs controls; no numeric VCEP enrichment threshold available for MUTYH

Evidence considered

• ClinVar record ClinVarID 187040 (VCV 187040, NM_001048174.2(MUTYH):c.1392+2C>T, exact match): aggregate classification Uncertain significance, review status 'criteria provided, single submitter'; 17 submissions (10 Uncertain significance, 2 Benign, 2 Likely benign, 1 Likely pathogenic, 1 Uncertain Significance capitalised separately); 0 expert-panel submissions. No proband or control counts are exposed, so this is not case-control enrichment evidence.
• Full-text search of all seven papers retrieved for this case (PMID:25186627, PMID:25356965, PMID:25394175, PMID:25452455, PMID:25645574, PMID:25741868, PMID:26467025) for 'c.1476+2C>T', '1476+2C>T', 'c.1392+2C>T' and '1392+2C>T' returned zero occurrences in every file.
• PMID:25186627 (Tung et al. 2015): 25-gene hereditary cancer panel in 2158 breast-cancer probands; only biallelic MUTYH carriers counted as incidental findings (2 patients); 42 monoallelic MUTYH carriers; no MUTYH variant is named anywhere in the paper, so it contributes no variant-level case count.
• gnomAD v4.1 (GRCh38 chr1-45331180-G-A): AF 8.11568e-05, 131/1,614,160 alleles, 0 homozygotes, grpmax FAF 0.00107164, popmax African/African American AF 0.00127898 (96/75,060). gnomAD v2.1: AF 0.000130794, 37/282,888 alleles, 0 homozygotes, popmax African/African American AF 0.0010813 (27/24,970). gnomAD v2.1 non-cancer exomes AF 0.000122389 (29/236,950); gnomAD v3.1 non-cancer AF 0.000324412 (48/147,960). Variant absent from gnomAD-Canada v1.0. The variant is therefore demonstrably present in population (control) samples with no homozygotes observed.
• No numeric comparison was made for PS4: the governing framework (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP MUTYH v1.0, CSpec doc 1742141534) publishes no PS4 rule text, and the generic ACMG/AMP 2015 PS4 definition carries no numeric threshold, so there was no operator (>= or <=) to quote and no inequality to evaluate.

Still missing

• Three cohort/panel papers cited on the ClinVar page for this record (PMID:28873162 universal tumor/normal sequencing, PMID:29684080 Cowden/Bannayan-Riley-Ruvalcaba panel, PMID:33471991 Breast Cancer Association Consortium) were never fetched into this case, so their full texts are unavailable; only their titles were seen. None of the seven full texts that WERE retrieved mentions the variant, and panel-cohort membership alone would not establish statistically significant enrichment, but a reviewer with access to those three papers could confirm the absence of this exact variant.
• No per-criterion numeric threshold for PS4 (or any criterion in this group) is available from the governing VCEP source: the InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) renders no criteria codes and is marked 'Classification Rules In Prep', so generic ACMG/AMP 2015 (which defines no PS4 numeric cutoff) was applied.

Sources

Reasoning

PM2 (supporting) requires the variant to be absent from, or at an extremely low frequency in, population databases, applied here with the supplied supporting-strength threshold of <=0.0001 (SVI recommendation to downgrade PM2 to supporting, PMID:25741868). No gene-specific PM2 rule or gene-specific population source could be applied: the governing InSiGHT Hereditary Colorectal Cancer/Polyposis specification for MUTYH v1.0 (CSPEC doc 1742141534) is the applicable framework but its retrieved criterion payload is empty, so the all-comers gnomAD totals are the default source. On those totals the result is split by dataset: gnomAD v2.1 all-comers AF 0.000130794 (37/282,888 alleles) is above the 0.0001 threshold, while gnomAD v4.1 all-comers AF 0.0000812 (131/1,614,160 alleles) falls marginally below it. The apparent v4.1 drop is a dataset-composition artifact (a four-fold larger allele number dilutes the same rare variant) rather than a genuinely lower frequency, and the ancestry-resolved and filtering-AF statistics - which are the appropriate way to judge rarity for a variant with a marked ancestry skew - are decisively above the threshold: African/African American AF 0.0010813 (v2.1) and 0.00127898 (v4.1), and gnomAD grpmax filtering AF 0.00081502 (v2.1), 0.00107164 (v4.1), 0.00083458 (v2.1 non-cancer exomes) and 0.00079083 (v3.1 non-cancer genomes), i.e. roughly 8- to 13-fold the 0.0001 cutoff. The non-cancer subsets agree with the all-comers data (AF 0.000122389 and 0.000324412 respectively) and do not lower the frequency. In other words, this variant is carried by about 1 in 800 African-ancestry alleles, is observed on 131 alleles in gnomAD v4.1, and is not absent from any population group; treating it as 'absent/very rare' at the 0.0001 level would be a threshold artifact. PM2 is therefore not met. Human review is flagged only because the single all-comers v4.1 total (0.0000812) sits nominally just under the cutoff while every ancestry-resolved and filtering-frequency statistic exceeds it.

Rule

PM2 (supporting): allele frequency <= 0.0001 (ClinGen SVI recommendation to downgrade PM2 to supporting, PMID:25741868); no gene-specific VCEP threshold available for MUTYH.

Evidence considered

• gnomAD v4.1 all-comers (default source): total AF 0.0000812 (131/1,614,160 alleles), exome AF 0.0000540 (79/1,461,824), genome AF 0.0003414 (52/152,336), homozygotes 0; grpmax filtering AF 0.00107164; African/African American AF 0.00127898 (96/75,060).
• gnomAD v2.1 all-comers (default source): total AF 0.000130794 (37/282,888 alleles), exome AF 0.000119290 (30/251,488), genome AF 0.000222930 (7/31,400), homozygotes 0; grpmax filtering AF 0.00081502; African/African American AF 0.0010813 (27/24,970), AFR_XX 0.001309091.
• gnomAD v2.1 non-cancer exomes (exomes-only figures, cancer cohorts excluded): AF 0.000122389 (29/236,950 alleles), African/African American AF 0.001100949 (26/23,616), grpmax filtering AF 0.00083458, homozygotes 0 - concordant with the all-comers totals and not lower.
• gnomAD v3.1 non-cancer genomes (v3 has no exome cohort): AF 0.000324412 (48/147,960 alleles), grpmax filtering AF 0.00079083, homozygotes 0 - again above the 0.0001 threshold.
• gnomAD-Canada v1.0 (HostSeq genomes): variant absent.
• PM2 was applied with the supplied generic threshold of <=0.0001 at supporting strength, attributed to the ClinGen SVI recommendation to downgrade PM2 to supporting (PMID:25741868); no MUTYH-specific PM2 threshold or gene-specific source preference could be substituted because the applicable InSiGHT specification (CSPEC doc 1742141534, version 1.0, preferred transcript NM_001128425.2, autosomal recessive, MONDO:0012041) returned an empty criteria list.
• Ancestry and dataset-size reasoning: the v4.1 total AF is nominally below 0.0001 only because the allele number is ~5.7x larger than v2.1 (1,614,160 vs 282,888) while the variant remains concentrated in the African/African American group (96 of 131 carriers); the ancestry-resolved frequencies and grpmax filtering AF (~0.0008-0.0013) show the variant is not rare at the population level, which is the circumstance PM2 is intended to exclude.

Still missing

• The governing InSiGHT MUTYH specification v1.0 (CSPEC doc 1742141534) returned an empty criteria list, so no gene-specific PM2 rule, strength or gene-specific (non-cancer/exome-only) population source could be applied; the all-comers gnomAD totals were used as the default source.
• PM2 verdict is borderline on one statistic only: gnomAD v4.1 all-comers total AF 0.0000812 is just below the generic 0.0001 threshold, while gnomAD v2.1 all-comers (0.000130794) and all ancestry-resolved/grpmax filtering values (0.00079-0.00128) are above it; a reviewer with the MUTYH VCEP thresholds or a MAP-specific maximum credible allele frequency should confirm the final PM2 call.
• No MUTYH-associated polyposis prevalence-based maximum credible allele frequency (e.g. from a gene-specific specification or a prevalence publication) was available in this case bundle to calibrate PM2/BS1 for a recessive disorder.

Sources

Reasoning

PP5 is triggered only when the exact variant carries a ClinVar expert-panel (ClinGen VCEP / expert-panel) classification of Pathogenic or Likely pathogenic. For MUTYH NM_001128425.2:c.1476+2C>T the ClinVar record ClinVarID 187040 (matched exactly at the transcript level to NM_001048174.2:c.1392+2C>T, match_score 16) has 0 expert-panel submissions out of 17 total submissions: every submission was audited with is_expert_panel = false, and the record's review status is 'criteria provided, single submitter' (one star), not the expert-panel three-star status. The submitters are ordinary clinical laboratories and health systems (Ambry Genetics, GeneDx, Invitae/Labcorp, Color Health, Counsyl, Blueprint Genetics, Mendelics, Sema4, Quest Diagnostics, LabCorp Women's Health, All of Us Research Program, PreventionGenetics, Rigshospitalet, Sinai Health System). The record does contain one Likely pathogenic submission from a single clinical laboratory, but an ordinary laboratory assertion must never trigger PP5, and the aggregate ClinVar classification is Uncertain significance, which is in any case not a Pathogenic/Likely pathogenic assertion. The criterion's prerequisite is therefore unmet. No numeric threshold or comparison applies to PP5 in this case: the governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) publishes no criteria codes for this case, and PP5 is a categorical criterion with no operator to quote.

Rule

PP5 (Richards et al. 2015, PMID:25741868) as constrained for this group: only an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification supports PP5; ordinary laboratory submissions, aggregate labels, and non-expert assertions never trigger it

Evidence considered

• ClinVar submission audit for ClinVarID 187040: 17 submissions, exact_variant_match true for all, expert_panel_submissions = 0; each submission record carries is_expert_panel = false (submitters include Ambry Genetics, GeneDx, Invitae/Labcorp, Color Health, Counsyl, Blueprint Genetics, Mendelics, Sema4, Quest Diagnostics, LabCorp Women's Health, All of Us Research Program, PreventionGenetics, Rigshospitalet, Sinai Health System).
• ClinVar record-level classification Uncertain significance with review status 'criteria provided, single submitter'; expert panel list is empty; the single Likely pathogenic submission belongs to one ordinary clinical laboratory and the aggregate record is not Pathogenic/Likely pathogenic.
• PP5 was not applied: the criterion requires an exact-variant expert-panel Pathogenic/Likely pathogenic assertion, which does not exist for this variant in ClinVar.

Still missing

• The governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) exposes no criteria text, so it could not be confirmed whether that VCEP overrides or additionally constrains PP5; the generic ACMG/AMP 2015 PP5 definition and the exact-variant expert-panel rule were applied instead.

Sources

Reasoning

BA1 requires a stand-alone benign allele frequency of >=0.05 (ACMG/AMP 2015, PMID:25741868). No queried population source approaches this. gnomAD v2.1 all-comers: AF 0.000130794 (37/282,888 alleles), grpmax filtering AF 0.00081502; gnomAD v4.1 all-comers: AF 0.0000812 (131/1,614,160 alleles), grpmax filtering AF 0.00107164. The highest ancestry-specific frequency is African/African American: 27/24,970 alleles (AF 0.0010813) in v2.1 and 96/75,060 alleles (AF 0.00127898) in v4.1 - roughly 40- to 60-fold below the 0.05 threshold. The non-cancer subsets are concordant (v2.1 non-cancer exomes AF 0.000122389; v3.1 non-cancer genomes AF 0.000324412), and the variant is absent from gnomAD-Canada v1.0. No homozygotes are reported in any dataset (homozygote count 0 throughout), and no founder-effect population with a materially higher frequency is evident. MUTYH-associated polyposis (MONDO:0012041) is autosomal recessive; even allowing for a recessive disease model and for the higher carrier frequencies tolerated in AR genes, no observed frequency is remotely compatible with a stand-alone benign call. The governing InSiGHT MUTYH specification v1.0 was checked first but its retrieved criterion payload is empty, so the generic ACMG/AMP stand-alone threshold applies.

Rule

BA1 (stand-alone): allele frequency >= 0.05 in a population database (ACMG/AMP 2015, PMID:25741868).

Evidence considered

• gnomAD v4.1 all-comers (GRCh38 chr1-45331180-G-A): total AF 0.0000812 (131/1,614,160 alleles), homozygotes 0; exome AF 0.0000540 (79/1,461,824), genome AF 0.0003414 (52/152,336); grpmax filtering AF 0.00107164; highest ancestry group African/African American AF 0.00127898 (96/75,060).
• gnomAD v2.1 all-comers (GRCh37 1-45796852-G-A): total AF 0.000130794 (37/282,888 alleles), homozygotes 0; exome AF 0.000119290 (30/251,488), genome AF 0.000222930 (7/31,400); grpmax filtering AF 0.00081502; highest ancestry group African/African American AF 0.0010813 (27/24,970).
• gnomAD v2.1 non-cancer exomes (exomes-only figures, NFE/AFR/etc. re-derived without cancer cohorts): AF 0.000122389 (29/236,950 alleles), homozygotes 0; African/African American AF 0.001100949 (26/23,616); grpmax filtering AF 0.00083458. This source was inspected because some specifications calibrated against non-cancer populations specify it for the frequency criteria; it does not change any verdict and is reported here for completeness.
• gnomAD v3.1 non-cancer genomes (v3 has no exome cohort, so all 147,960 alleles are genomes): AF 0.000324412 (48/147,960 alleles), homozygotes 0; grpmax filtering AF 0.00079083. The single highest sub-cohort value in this dataset, 4/132 alleles (AF 0.030303) in 1KG:LWK, is discussed under BS1.
• gnomAD-Canada v1.0 (HostSeq genomes): variant absent.
• The variant is present in ClinVar (variation ID 187040) but ClinVar does not supply population allele frequencies, so it contributes no BA1 evidence.
• BA1 definition and the 0.05 stand-alone frequency threshold are taken from the ACMG/AMP 2015 standards (Richards et al., PMID:25741868).
• Governing framework check: the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for MUTYH v1.0 (CSPEC doc 1742141534, https://cspec.genome.network/cspec/ui/svi/doc/1742141534) is the applicable gene-specific framework for this case, but the retrieved specification contains no criterion-level rules (empty criteria list), so no VCEP-specified BA1 threshold or VCEP-specified population source (non-cancer or exome-only) exists to override the all-comers totals used above.

Still missing

• No gene-specific BA1 allele-frequency threshold is available: the InSiGHT Hereditary Colorectal Cancer/Polyposis specification for MUTYH v1.0 (CSPEC doc 1742141534) was located but returned an empty criteria list, so the generic 0.05 stand-alone threshold was applied.
• Frequency data are limited to gnomAD v2.1, v4.1, v2.1 non-cancer exomes, v3.1 non-cancer genomes and gnomAD-Canada (absent); no population-frequency data specific to MUTYH-associated polyposis cohorts were available.

Sources

Reasoning

BS1 requires an allele frequency greater than expected for the disorder, applied here with the supplied generic default threshold of >=0.01 (generic SVI/Whiffin derivation, PMID:28518168; no gene-specific BS1 threshold exists because the retrieved InSiGHT MUTYH specification v1.0 has an empty criterion payload). The relevant summary statistic is the ancestry-based frequency, since masking a high-frequency ancestry is the failure mode this criterion guards against. The highest ancestry-specific frequency observed anywhere is African/African American: AF 0.0010813 (27/24,970) in gnomAD v2.1 and 0.00127898 (96/75,060) in gnomAD v4.1, with gnomAD grpmax filtering AF 0.00081502 (v2.1) and 0.00107164 (v4.1). Non-cancer subsets are concordant: v2.1 non-cancer exomes AFR AF 0.001100949 (grpmax FAF 0.00083458) and v3.1 non-cancer genomes grpmax FAF 0.00079083. Every one of these values sits about 8- to 13-fold below the 0.01 threshold. The only figure above 0.01 in the entire dataset set is 4/132 alleles (AF 0.030303) in the 1KG:LWK sub-cohort reported within gnomAD v3.1 non-cancer; that is a 132-allele, founder-enriched 1000 Genomes reference sub-sample that is inconsistent with the much better-powered AFR estimate in v4.1 (96/75,060 = 0.128%) and is excluded from gnomAD's own grpmax filtering AF (0.00079083) - it is a small-sample threshold artifact, not evidence of a common benign allele, and it is not used to meet BS1. Disease-prevalence reasoning points the same way: MUTYH-associated polyposis is an autosomal recessive, early-onset high-penetrance polyposis syndrome with a prevalence on the order of 1 in 20,000-40,000 (carrier frequency roughly 1-1.4%), so a single allele at ~0.13% in African-ancestry individuals is well within the range compatible with a pathogenic recessive allele rather than exceeding it. BS1 is not met.

Rule

BS1 (strong): allele frequency >= 0.01 - generic SVI default threshold (Whiffin et al. 2017, PMID:28518168); no gene-specific VCEP threshold available.

Evidence considered

• gnomAD v4.1 all-comers: total AF 0.0000812 (131/1,614,160 alleles); African/African American AF 0.00127898 (96/75,060); grpmax filtering AF 0.00107164; homozygotes 0.
• gnomAD v2.1 all-comers: total AF 0.000130794 (37/282,888 alleles); African/African American AF 0.0010813 (27/24,970); grpmax filtering AF 0.00081502; homozygotes 0.
• gnomAD v2.1 non-cancer exomes: AF 0.000122389 (29/236,950 alleles); African/African American AF 0.001100949 (26/23,616); grpmax filtering AF 0.00083458; homozygotes 0.
• gnomAD v3.1 non-cancer genomes: AF 0.000324412 (48/147,960 alleles); grpmax filtering AF 0.00079083; the highest single sub-cohort is 1KG:LWK at 4/132 alleles (AF 0.030303), considered and rejected as a 132-allele small-sample outlier inconsistent with the 96/75,060 AFR frequency in v4.1.
• No dataset reports a homozygote (homozygote count 0 in gnomAD v2.1, v4.1, v2.1 non-cancer exomes and v3.1 non-cancer genomes), and the variant is absent from gnomAD-Canada v1.0.
• BS1 was applied with the supplied generic default threshold of >=0.01; that generic SVI default is attributed to Whiffin et al. 2017 (PMID:28518168), and no MUTYH-specific threshold could be substituted because the applicable InSiGHT specification (CSPEC doc 1742141534) returned no criterion-level rules.
• Disease model considered in interpreting the threshold: MUTYH-associated polyposis is autosomal recessive (per the InSiGHT/CSPEC gene definition, MONDO:0012041, preferred transcript NM_001128425.2), with high penetrance and early onset, so a modest population frequency is compatible with a pathogenic recessive allele and does not by itself support BS1.
• BA1/BS1 frequency framing (frequency greater than expected for the disorder) is taken from the ACMG/AMP 2015 standards (PMID:25741868).

Still missing

• No gene-specific (MUTYH/InSiGHT) BS1 frequency threshold is available - the retrieved specification has an empty criteria list - so the generic 0.01 default was used; a prevalence-derived BS1 cutoff for MUTYH-associated polyposis could not be computed from any source in this case.
• The 1KG:LWK sub-cohort value of 4/132 (3.03%) in gnomAD v3.1 non-cancer is above the generic BS1 threshold; it was rejected as a small-sample artifact, but a reviewer with access to the raw gnomAD sub-cohort data or to population-specific MAP prevalence data may wish to confirm this.
• No case-control or control-cohort frequency data for this variant were found in the literature retrieved for this case; the papers available do not name the variant.

Sources

Reasoning

BS2 is applicable to a recessive disorder such as MUTYH-associated polyposis: it requires observation of the variant in a homozygous (or biallelic) state in a healthy adult, given full penetrance expected at an early age (ACMG/AMP 2015, PMID:25741868). Homozygote counts are 0 in every population source queried: gnomAD v2.1 (0 homozygotes over 282,888 alleles, including 0 among the 27 AFR carriers), gnomAD v4.1 (0 over 1,614,160 alleles, including 0 among the 96 AFR carriers), gnomAD v2.1 non-cancer exomes (0) and gnomAD v3.1 non-cancer genomes (0, including the 4 1KG:LWK carriers). The variant is also absent from gnomAD-Canada v1.0, and none of the full-text papers retrieved for this case report the variant at all, so no published homozygous healthy adult carrier was identified. BS2 is therefore not met. Importantly, the absence of homozygotes must not be read as evidence of tolerance: with allele frequencies of ~0.0000812 (v4.1) to ~0.00128 (AFR), the Hardy-Weinberg expectation is far less than one homozygote in every available dataset (roughly 0.005 expected homozygotes in v4.1's 807,080 individuals), so the observation is uninformative in both directions rather than affirmative evidence.

Rule

BS2 (strong): observed in a homozygous/biallelic state in a healthy adult individual for a recessive disorder with full penetrance expected at an early age (ACMG/AMP 2015, PMID:25741868); not met when no homozygotes are observed.

Evidence considered

• gnomAD v4.1 all-comers: homozygote count 0 over 1,614,160 alleles (exomes 0/1,461,824; genomes 0/152,336); no homozygotes in any ancestry group, including African/African American (0 among 96 carriers).
• gnomAD v2.1 all-comers: homozygote count 0 over 282,888 alleles (exomes 0/251,488; genomes 0/31,400); no homozygotes in any ancestry group, including African/African American (0 among 27 carriers).
• gnomAD v2.1 non-cancer exomes: homozygote count 0 (29 carriers among 236,950 alleles).
• gnomAD v3.1 non-cancer genomes: homozygote count 0 (48 carriers among 147,960 alleles).
• gnomAD-Canada v1.0 (HostSeq genomes): variant absent, so no homozygous carrier there either.
• Hardy-Weinberg expectation check: at the observed all-comers frequencies (AF 0.0000812 in v4.1; 0.000130794 in v2.1) the expected number of homozygotes in the available sample sizes is <<1, so zero observed homozygotes is an expected finding and cannot be used as evidence against pathogenicity.
• The full-text papers extracted for this case (PMID:25186627, PMID:25356965, PMID:25394175, PMID:25452455, PMID:25645574, PMID:25741868, PMID:26467025) were checked and none names this variant, so no reported healthy homozygous adult carrier exists in the retrieved literature.
• BS2 definition (observed in a healthy adult individual for a recessive disorder, with full penetrance expected at an early age) is taken from the ACMG/AMP 2015 standards (PMID:25741868); the InSiGHT MUTYH specification v1.0 retrieved for this case contains no criterion-level BS2 rule.

Still missing

• No homozygous or biallelic carrier of this variant was identified in any queried population database or in the literature retrieved for this case; because the allele is rare the expected homozygote count is well below 1 in all datasets, so BS2 could not be affirmatively supported even with unlimited data of this type.
• No case-control genotype data for the variant are available; the papers reviewed contain no variant-level information and do not mention c.1476+2C>T.

Sources

Reasoning

BS3 requires well-established functional studies - with adequate assay controls and biological relevance - showing no damaging effect on protein function or splicing (Richards et al. 2015, PMID:25741868). The governing MUTYH specification is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification V1.0 (cspec), which was retrieved for this case but returned as an unstructured ruleset with an empty criteria payload (framework_complete=false, rule_payload={}); no gene-specific BS3 rule exists, so the generic ACMG/AMP 2015 definition applies. No functional assay of NM_001128425.2:c.1476+2C>T was identified in any source examined: literature triage listed no BS3-indexed paper, the full texts available for this case (PMID:25186627, PMID:25356965, PMID:25394175, PMID:25452455, PMID:25645574, PMID:25741868) contain no assay data on this variant, and ClinVar submitters explicitly record that functional studies have not been reported (SCV000697679 LabCorp: '...these predictions have yet to be confirmed by functional studies'; SCV004817134 All of Us: 'to our knowledge, functional studies have not been reported for this variant'). Computational tools predicting that the variant strengthens the canonical 5' donor site are in-silico output, not a functional assay, and do not demonstrate a normal-function outcome; the SpliceAI delta of 0.257 in fact predicts partial loss of the donor site. There is therefore no RNA- or protein-level evidence that this canonical +2 change is tolerated, and BS3 strength calibration is not applicable in the absence of any validated assay and its likelihood ratio. BS3 is not met on absence of evidence. The ClinVar classification of this variant was not used to infer this criterion.

Rule

ACMG/AMP 2015 BS3 (Richards et al., PMID:25741868): requires well-established functional studies showing no damaging effect; no gene-specific BS3 rule in the InSiGHT MUTYH CSPEC V1.0 ruleset as retrieved (unstructured, empty criteria payload)

Evidence considered

• Governing framework: the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for MUTYH V1.0 (cspec) contains no structured BS3 rule as retrieved (unstructured ruleset, empty criteria payload), so the generic ACMG/AMP 2015 BS3 definition (Richards et al., PMID:25741868) was applied.
• PMID:25741868 defines BS3 as functional evidence showing no damaging effect on protein function or splicing, and notes that the actual impact of a splice-site variant must be established by RNA or protein analysis rather than prediction.
• ClinVar VCV000187040: no submitter reports a functional assay for this variant; SCV000697679 (LabCorp) notes the computational donor-site strengthening is as yet 'unconfirmed by functional studies', and SCV004817134 (All of Us Research Program) states 'to our knowledge, functional studies have not been reported for this variant'.
• No BS3-indexed paper was returned by literature triage, and no assay data on MUTYH c.1476+2C>T were found in the full texts retrieved for this case.
• Computational output (4/4 tools predicting a strengthened canonical 5' donor site; SpliceAI max delta 0.257) is not functional evidence and does not establish a no-damaging-effect outcome.
• The ClinVar aggregate classification (Conflicting classifications of pathogenicity) was not used to infer this criterion.

Still missing

• No functional assay reports normal splicing or normal MUTYH function for c.1476+2C>T; BS3 cannot be met without RNA- or protein-level evidence showing no damaging effect.
• No assay with validated controls and performance (likelihood ratio) exists for this variant, so BS3 strength calibration is not applicable.

Sources

Reasoning

BP4 (computational evidence of no impact; Richards et al. 2015, PMID:25741868) is in scope for this variant, because NM_001128425.2:c.1476+2C>T is an intronic splice-region (canonical splice-donor +2) change evaluated on the SpliceAI path rather than a missense variant. On that path the SpliceAI maximum delta score is 0.257, which is above the BP4 supporting cutoff of <= 0.1 (Jaganathan et al. 2019, Cell, PMID:30661751); the predicted effect is donor loss (DS_DL 0.257), so the predictor does not support a benign, splice-neutral interpretation and BP4 is not met. The benign or intermediate result is not rescued by any other predictor: REVEL has no score for this position, and returning to the missense path would be inappropriate for a non-missense variant. The governing ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for MUTYH v1.0 (CSPEC doc 1742141534) was checked first and supplies no BP4 rule or pre-assigned benign computational code and no gene-specific PP3/BP4 lookup table, so the generic ClinGen SVI SpliceAI calibration was used. As with PP3, the same lookup's unusually low donor-loss delta for a canonical +2 change means the underlying score is worth confirming before it is used to withhold benign support.

Rule

SpliceAI max delta <= 0.1 -> BP4 supporting (Jaganathan et al. 2019, Cell, PMID:30661751).

Evidence considered

• SpliceAI lookup for NM_001128425.2:c.1476+2C>T / chr1:45796852 G>A (hg19): max delta score 0.257, driven by donor loss (DS_DL 0.257; DS_AG 0.049, DS_AL 0.001, DS_DG 0.084), which exceeds the BP4 supporting cutoff of <= 0.1.
• SpliceAI online lookup screenshot (hg19, Gencode basic, max distance 500) confirming Donor Loss 0.26 and Acceptor Loss 0.05 for this variant on transcript NM_001128425.2.
• Path selection: the variant is intronic/splice-region, so BP4 was assessed on the SpliceAI path only; no REVEL score exists for this position and BayesDel (-0.0838218) was not used as it has no established published ACMG-strength calibration for BP4.
• Thresholds applied verbatim: SpliceAI BP4 supporting <= 0.1, with PP3 supporting >= 0.2 and moderate >= 0.5 (Jaganathan et al. 2019, Cell, PMID:30661751).
• Governing-framework check: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP MUTYH v1.0 (CSPEC doc 1742141534) retrieved and inspected; it provides no BP4 rule text and no computational-code lookup table, so the generic ClinGen SVI calibration was used.
• Full-text/finding extracts available for this case (PMID:25186627, 25356965, 25394175, 25452455, 25645574, 25741868, 26467025) contain no splice-prediction or BP4-related data for this variant.

Still missing

• No VCEP-specific BP4 threshold or pre-assigned benign computational code is retrievable for MUTYH: the InSiGHT MUTYH v1.0 specification is present but yields no criteria text or PP3/BP4 rule, so generic ClinGen SVI SpliceAI calibration governs this call.
• The SpliceAI donor-loss delta (0.257) is low for a canonical +2 donor change; if the lookup value is corrected upward the BP4 conclusion would not change, but reviewer confirmation of the score is advisable.

Sources

Reasoning

BP6 is triggered only when the exact variant carries a ClinVar expert-panel (ClinGen VCEP / expert-panel) classification of Benign or Likely benign. For MUTYH NM_001128425.2:c.1476+2C>T the ClinVar record ClinVarID 187040 (exact transcript-level match to NM_001048174.2:c.1392+2C>T) has 0 expert-panel submissions out of 17: every audited submission has is_expert_panel = false, and the record's review status is 'criteria provided, single submitter', which is not expert-panel status. The record does contain non-expert Benign submissions (2 clinical laboratories: Ambry Genetics, GeneDx) and non-expert Likely benign submissions (2 clinical laboratories: Color Health, Invitae/Labcorp), but per the rule applied here ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6, and the record-level aggregate classification is Uncertain significance, not Benign/Likely benign. The criterion's prerequisite is therefore unmet. No numeric threshold or comparison applies: the governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) publishes no criteria text for this case, and BP6 is categorical, so there is no operator to quote.

Rule

BP6 (Richards et al. 2015, PMID:25741868) as constrained for this group: only an exact-variant ClinVar expert-panel Benign/Likely benign classification supports BP6; ordinary laboratory submissions, aggregate labels, and non-expert assertions never trigger it

Evidence considered

• ClinVar submission audit for ClinVarID 187040: 17 submissions, expert_panel_submissions = 0, is_expert_panel = false for every submission; record review status 'criteria provided, single submitter'.
• Non-expert benign-direction submissions present but disregarded under the applied rule: Benign from Ambry Genetics (SCV000217536) and GeneDx (SCV001866249); Likely benign from Color Diagnostics/Color Health (SCV000685586) and Labcorp Genetics/Invitae (SCV000545716). The record-level aggregate is Uncertain significance (10 laboratories).
• BP6 was not applied: no exact-variant expert-panel Benign/Likely benign classification exists for this variant in ClinVar.

Still missing

• The governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) exposes no criteria text for this case, so a VCEP-specific override of BP6 could not be checked; the generic ACMG/AMP 2015 BP6 definition plus the exact-variant expert-panel rule were applied.

Sources

Reasoning

PS2 requires that the variant be confirmed de novo in an affected proband, with parental testing demonstrating that neither biological parent carries it (Richards et al. 2015, PMID:25741868). The governing specification for this gene is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for MUTYH v1.0 (cspec, doc 1742141534), which records autosomal recessive inheritance (familial adenomatous polyposis 2, MONDO:0012041) but exposes no parsed criterion-level rules (criteria list empty, framework_complete=false), so the generic ACMG/AMP 2015 criterion definitions apply. This case contains only the variant itself (MUTYH NM_001128425.2:c.1476+2C>T / NC_000001.10:g.45796852G>A); there is no proband, no affected individual, and no parental genotype data in any source examined (case summary, ClinVar record 187040 and its 17 submissions, the full evidence and prefetch records, and all seven fetched publications). Because the proband and the transmitting-parent genotypes that PS2 is defined around do not exist in this case, PS2 cannot be evaluated; it is not a negative result, it is an unassessable one. The autosomal recessive mechanism of MUTYH-associated polyposis would additionally make a single confirmed de novo allele an unusual route to disease, so even with parental testing PS2 would require biallelic confirmation.

Evidence considered

• Governing framework: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification located (doc_id 1742141534) but its parsed criteria list is empty and framework_complete=false, so generic ACMG/AMP 2015 definitions apply; the ruleset records mode of inheritance 'Autosomal recessive inheritance' for familial adenomatous polyposis 2 (MONDO:0012041).
• Criterion definition: PS2 = de novo (confirmed with parental testing) in a patient with the disease and no family history (Richards et al. 2015, PMID:25741868).
• Case content searched: no occurrence of 'proband', 'pedigree', 'family', 'de novo', 'maternal', 'paternal', or 'meioses' appears in case_summary.json, evidence.json, prefetch.json, review_manifest.json, source_registry.json, literature_pass.json, fulltext_map.json or paper_extracts.json for this case.
• ClinVar record 187040: 17 submissions, all variant-level classifications (Uncertain significance, Benign, Likely benign, Likely pathogenic); no submitting laboratory reports a family, pedigree, proband genotype, or parental testing result, and no expert-panel submission is present.
• Fetched literature (7 full texts, all variant_mentioned=false): none reports c.1476+2C>T in any patient, and none reports parental testing for this variant.

Still missing

• No proband/affected individual is defined in this case; no clinical phenotype or family record is provided.
• No parental (maternal/paternal) genotype testing exists for the variant, so de novo status cannot be established or excluded.
• No biallelic status information (second MUTYH allele, phase) is available, which is required to relate a de novo event to MUTYH-associated polyposis (autosomal recessive).

Sources

Reasoning

The governing specification for this gene is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MUTYH, Version 1.0 (doc 1742141534), which establishes autosomal-recessive inheritance for MUTYH-associated polyposis (familial adenomatous polyposis 2, MONDO:0012041) but carries no criterion-level PM3 rule text; generic ACMG/AMP PM3 (Richards et al. 2015, PMID:25741868) therefore applies: for a recessive disorder, the variant must be detected in trans with a pathogenic (or likely pathogenic) variant in an affected individual. NM_001128425.2:c.1476+2C>T is a canonical +2 donor splice variant in MUTYH for which no constitutional genotype, carrier status, family study, or phase-resolving data exist in this case: no proband is described, no second MUTYH variant was identified in the collected evidence, and the audited ClinVar record (variation 187040; 17 submissions, none from an expert panel) provides no in-trans or phase-resolved observation for this variant. The papers linked to this variant through ClinVar do not supply the missing allele-level data: PMID:25186627 reports two patients with biallelic MUTYH mutations but names no specific MUTYH allele, and PMID:25452455 describes MUTYH-associated polyposis only at the gene level. An affected-proband observation alone, without resolved phase and a pathogenic partner allele, does not establish the required in-trans configuration, so PM3 cannot be assigned from the available evidence and is left unassessed pending allele-level carrier data.

Rule

Generic ACMG/AMP PM3 (PMID:25741868): for a recessive disorder, the variant is detected in trans with a pathogenic or likely pathogenic variant; definitive phase and pathogenicity of the partner allele are required.

Evidence considered

• The ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification v1.0 designates MUTYH-associated polyposis (familial adenomatous polyposis 2) as autosomal recessive but contains no criterion-level PM3 rule, so the generic ACMG/AMP PM3 definition was applied.
• Generic PM3 for a recessive disorder requires the variant under assessment to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual; neither an affected-proband observation alone nor an unresolved compound-heterozygous state satisfies it.
• No proband genotype, carrier status, second MUTYH variant, family study, or phase-resolving assay for NM_001128425.2:c.1476+2C>T is present in this case, so the in-trans prerequisite could not be evaluated.
• The audited ClinVar submissions for variation 187040 (17 submissions; classifications ranging from Benign to Likely pathogenic; no expert-panel submission) report no phase-resolved or in-trans observation for this variant.
• PMID:25186627, cited as a criterion lead by ClinVar submitters, identified biallelic MUTYH mutations in two patients but names no specific MUTYH allele, so it provides no in-trans evidence for this variant.

Still missing

• Proband or carrier genotype showing NM_001128425.2:c.1476+2C>T in trans with a pathogenic or likely pathogenic MUTYH variant, with phase confirmed by family study, allele-specific testing, or long-read phasing.
• Pathogenicity assessment of any partner MUTYH allele identified on the opposite chromosome.

Sources

Reasoning

PM6 covers an assumed de novo occurrence in a patient with the disease when parental confirmation of non-carrier status is unavailable (Richards et al. 2015, PMID:25741868); it still requires an affected proband and some clinical/parental context from which de novo status is inferred. The applicable gene framework for this case is the ClinGen InSiGHT MUTYH v1.0 specification (cspec, doc 1742141534), which provides no parsed criterion-level rules (criteria list empty, framework_complete=false), so generic ACMG/AMP 2015 definitions apply. This case is a variant-level record only: no proband is defined, no phenotype is recorded, and no parental samples or family history are available in any examined source (case summary, ClinVar record 187040 and its submissions, evidence.json, prefetch.json, and the seven fetched publications, none of which mention the variant). Without an affected individual or any parental context, 'assumed de novo' cannot be established even at supporting strength, so PM6 is unassessable rather than negative.

Evidence considered

• Criterion definition: PM6 = assumed de novo, without confirmation of parentage (Richards et al. 2015, PMID:25741868).
• Governing framework: InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 (cspec doc 1742141534) located, but no parsed criterion-level rules are exposed (criteria list empty; framework_complete=false), and the ruleset specifies autosomal recessive inheritance for MUTYH-associated polyposis.
• Case content searched: no proband, phenotype, family history, parental testing, or de novo statement is present in any case file (case_summary.json, evidence.json, prefetch.json, vcep_materials.json, review_manifest.json, source_registry.json, literature_pass.json, fulltext_map.json, paper_extracts.json).
• ClinVar record 187040 (17 submissions, no expert panel) contains only variant-level classifications with no proband, parental or family information.
• Fetched literature (7 full texts, all variant_mentioned=false): none reports c.1476+2C>T in a patient, and none provides parental or family context for this variant.

Still missing

• No affected proband or phenotype annotation is present in this case, which PM6 requires as its starting point.
• No parental or family-history information is available from which a de novo origin could be assumed when parental testing is absent.
• Whether the variant is biallelic with a second MUTYH variant (compound heterozygous) is not recorded.

Sources

Reasoning

PP1 requires co-segregation of the variant with disease in multiple affected family members, scored from the number of informative meioses across a pedigree (Richards et al. 2015, PMID:25741868). The governing framework for this gene is the ClinGen InSiGHT MUTYH v1.0 specification (cspec, doc 1742141534), which records autosomal recessive inheritance but exposes no parsed criterion-level rules (criteria list empty; framework_complete=false), so generic ACMG/AMP 2015 definitions apply. No pedigree, no affected relative pair, and no informative meiosis for this variant exists in any source examined: the case is a single-variant record, the ClinVar submissions (record 187040) are variant-level classifications with no family data or expert-panel review, and none of the seven fetched publications reports c.1476+2C>T in any individual, affected or unaffected. With zero families and zero meioses, PP1 is unassessable rather than negative.

Evidence considered

• Criterion definition: PP1 = co-segregation with disease in multiple affected family members, strength scaled by informative meioses (Richards et al. 2015, PMID:25741868).
• Governing framework: InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 (cspec doc 1742141534) located; parsed criteria list is empty and framework_complete=false, so the generic ACMG/AMP 2015 criterion applies.
• Case content searched: the words 'segregation', 'pedigree', 'family', 'proband', 'meiosis/meioses' appear nowhere in this case's evidence other than in the boilerplate triage note listing the criteria a paper collection may support; no family data is present.
• ClinVar record 187040: 17 submissions, no expert-panel submission, and no submitting laboratory reports co-segregation or a family.
• Fetched literature (7 full texts, all variant_mentioned=false): MUTYH is discussed only at gene/syndrome level (MAP is autosomal recessive; MAP was first described in three siblings in 2002), with no segregation data for c.1476+2C>T.

Still missing

• No pedigree or family record exists for this case.
• No affected or unaffected relatives have been genotyped for c.1476+2C>T, so the number of informative meioses is zero.
• No literature reports this exact variant in a family, so no external segregation data can be borrowed.

Sources

Reasoning

PP4 (Richards et al. 2015, PMID:25741868) requires that the patient's phenotype or family history be highly specific for a disease with a single genetic aetiology. This case contains no proband-level phenotypic data of any kind: no HPO terms, no clinical indication for testing, no pedigree, no family history, and no age or polyp-count information. The only phenotype-adjacent strings present are the ClinVar condition labels attached to the submission records, which are either empty or generic ('Not provided', 'not provided', 'MUTYH-related condition') and are submission-level, not proband-level. Assessing specificity is further complicated by the gene's inheritance model, which the governing framework states explicitly as autosomal recessive (familial adenomatous polyposis 2 / MUTYH-associated polyposis, MONDO:0012041), and by the fact that MUTYH-associated polyposis is also an attenuated polyposis syndrome that can mimic FAP and AFAP (PMID:25645574, PMID:25452455), so a polyposis phenotype is not by itself specific to MUTYH when APC testing has not been reported. Because the criterion's required input (a patient phenotype/family history) is absent rather than unfavourable, PP4 is recorded as not_assessed rather than not_met; no evidence in this case speaks for or against phenotype specificity for this variant.

Rule

generic ACMG/AMP 2015 PP4 (Richards et al. 2015, PMID:25741868): patient phenotype or family history highly specific for a disease with a single genetic aetiology

Evidence considered

• Absence of proband phenotype data in the case: the variant input is a bare HGVS string (NM_001128425.2:c.1476+2C>T) with no accompanying clinical description, HPO terms, pedigree, or testing indication.
• ClinVar submissions for ClinVarID 187040 carry only submission-level condition labels that are empty or generic ('Not provided', 'not provided', 'MUTYH-related condition'); no proband phenotype is exposed for any submission.
• Governing framework disease context: MUTYH-associated polyposis / familial adenomatous polyposis 2 (MONDO:0012041), autosomal recessive inheritance, preferred transcript NM_001128425.2 (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP MUTYH v1.0, CSpec doc 1742141534). The specification publishes no PP4 rule text.
• Phenotype-definition sources checked for specificity context: PMID:25394175 (referral guideline; MAP listed as the OMIM 608456 diagnosis to consider with >=10 cumulative adenomatous colon polyps), PMID:25452455 (MAP management mirrors FAP/AFAP; up to one third of biallelic carriers developed CRC without polyposis), PMID:25645574 (MAP is an attenuated polyposis syndrome that can mimic FAP or AFAP). None of these supplies patient-level data for this variant.

Still missing

• No proband phenotype, HPO term list, pedigree, family history, polyp count, age at diagnosis, or indication for testing is present anywhere in this case's evidence; PP4 cannot be evaluated without at least one of these.
• No per-criterion PP4 definition was retrievable from the governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534 exposes no criteria codes; rules listed as in prep), so the generic ACMG/AMP 2015 form of PP4 was applied.

Sources

Reasoning

BS4 requires an explicit lack of segregation: affected family members who do not carry the variant, in a pedigree with multiple informative meioses (Richards et al. 2015, PMID:25741868). The governing framework for this gene is the ClinGen InSiGHT MUTYH v1.0 specification (cspec, doc 1742141534), which exposes no parsed criterion-level rules (criteria list empty; framework_complete=false), so generic ACMG/AMP 2015 definitions apply. No family has been tested for this variant in this case: no pedigree is provided, the ClinVar submissions (record 187040) are variant-level classifications only and include no non-segregation claim, and none of the seven fetched publications mentions c.1476+2C>T at all, so no genotyped discordant affected relative exists. Absence of a family is not evidence of non-segregation, so BS4 cannot be asserted and is returned as unassessable.

Evidence considered

• Criterion definition: BS4 = lack of segregation in affected members of a family (Richards et al. 2015, PMID:25741868).
• Governing framework: InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 (cspec doc 1742141534) located; no parsed criterion-level rules are exposed (criteria list empty; framework_complete=false), so the generic ACMG/AMP 2015 criterion applies.
• Case content searched: no pedigree, family, proband, parental testing, or non-segregation statement appears in case_summary.json, evidence.json, prefetch.json, vcep_materials.json, review_manifest.json, source_registry.json, literature_pass.json, fulltext_map.json or paper_extracts.json.
• ClinVar record 187040: submissions include two classified Benign and two Likely benign, but the submissions contain no family, segregation or non-segregation evidence and no expert-panel review; they were not treated as BS4 evidence.
• Fetched literature (7 full texts, all variant_mentioned=false): no report of c.1476+2C>T in any individual, affected or unaffected, so no discordant-relative data exist.

Still missing

• No pedigree or family record exists for this case, so non-segregation cannot be observed.
• No affected relative has been genotyped and shown to lack c.1476+2C>T; a negative family study is required before BS4 could be applied.
• No published family study of this specific variant (segregating or non-segregating) is available among the sources examined.

Sources

Reasoning

The governing specification for this gene is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications for MUTYH, Version 1.0 (doc 1742141534), which establishes autosomal-recessive inheritance for MUTYH-associated polyposis but provides no criterion-level BP2 rule text; generic ACMG/AMP BP2 (Richards et al. 2015, PMID:25741868) therefore applies. Generic BP2 has two clauses: observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observation in cis with a pathogenic variant in any inheritance pattern. Because MUTYH disease is autosomal recessive (PMID:25452455 describes MUTYH-associated polyposis as an autosomal-recessive syndrome), the dominant-gene in-trans clause cannot apply, leaving only the cis clause. For NM_001128425.2:c.1476+2C>T there is no phase-resolved evidence of any kind: no co-occurring MUTYH variant on the same allele, no family study or allele-specific phasing, and no ClinVar submission or publication documenting the variant in cis with a pathogenic MUTYH variant. With the cis arrangement unestablished, BP2 cannot be assigned and is left unassessed.

Rule

Generic ACMG/AMP BP2 (PMID:25741868): observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern; the cis partner must itself be pathogenic or likely pathogenic.

Evidence considered

• The ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH specification v1.0 specifies autosomal-recessive inheritance for MUTYH-associated polyposis and contains no criterion-level BP2 rule, so the generic ACMG/AMP BP2 definition was applied.
• Generic BP2 requires either observation in trans with a pathogenic variant in a fully penetrant dominant gene/disorder (not applicable to this recessive gene) or observation in cis with a pathogenic variant under any inheritance pattern.
• No cis-phase information for NM_001128425.2:c.1476+2C>T was found: no co-occurring MUTYH variant, no family or allele-specific phasing data, and no reported haplotype carrying this change with a pathogenic MUTYH allele.
• ClinVar variation 187040 records uncertain, benign, likely benign and a single likely pathogenic assertion, none of which provides cis/trans phase information for this variant.

Still missing

• Phase-resolved evidence (family study, allele-specific testing, or long-read sequencing) showing NM_001128425.2:c.1476+2C>T in cis with a pathogenic or likely pathogenic MUTYH variant.
• Identification and classification of any co-occurring MUTYH variant on the same allele.

Sources

Reasoning

BP5 (Richards et al. 2015, PMID:25741868) requires that the variant be found in a case with an alternate molecular basis for disease - that is, a specific affected individual in whom a different genetic cause of the phenotype has been established. This case is a variant-level annotation with no proband: there is no clinical history, no co-occurring or second pathogenic variant reported, no segregation or co-segregation data, and no statement that any carrier had an alternative molecular diagnosis. The ClinVar submissions for ClinVarID 187040 record only classifications and generic condition labels, with no case descriptions, no accompanying variants, and no mention of an alternate molecular basis; gnomAD is population data and cannot supply a case with an alternate basis. Because the criterion's required input (a case with an established alternate molecular basis) is absent from the case rather than contradicted by it, BP5 is recorded as not_assessed rather than not_met. No numeric threshold or comparison applies to this criterion here: the governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534) publishes no criteria text for this case, and generic BP5 is categorical, so there is no operator to quote and no value to compare.

Rule

generic ACMG/AMP 2015 BP5 (Richards et al. 2015, PMID:25741868): variant found in a case with an alternate molecular basis for disease

Evidence considered

• Absence of case-level data: the case provides no proband clinical history, no second/co-occurring variant, no segregation data, and no statement of an alternate molecular basis for any carrier.
• ClinVar submissions for ClinVarID 187040 expose no case descriptions, no accompanying variants, and no alternate-diagnosis statements; condition labels are empty or generic.
• Governing framework: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP MUTYH v1.0, CSpec doc 1742141534 - identified as the applicable gene-specific specification, but it publishes no criteria text for this case, so generic ACMG/AMP 2015 BP5 was applied.

Still missing

• No proband, case description, accompanying variant, or alternate molecular diagnosis is available anywhere in this case's evidence; BP5 cannot be evaluated without at least one affected individual for whom an alternate genetic cause was established.
• No BP5 rule text was retrievable from the governing InSiGHT Hereditary Colorectal Cancer/Polyposis MUTYH v1.0 specification (CSpec doc 1742141534 renders no criteria codes; rules listed as in prep), so the generic ACMG/AMP 2015 form of BP5 was applied; any VCEP-specific numeric or likelihood-ratio reformulation of BP5 could therefore not be tested.

Sources