Variant classification summary

NM_001128425.2:c.1476+2C>T

MUTYH · NP_001121897.1:p.? · NM_001128425.2

GRCh37: chr1:45796852 G>A · GRCh38: chr1:45331180 G>A

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

PP3 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.?

gnomAD AF

8.11567626505427e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP3 supporting: SpliceAI maximum delta 0.257 exceeds the >=0.2 supporting cutoff but not the >=0.5 moderate cutoff.

2

PVS1 not met: the +2C>T change restores a consensus GT donor and the maximal exon 14 skip is in-frame (51 codons, no NMD).

3

PM2 not met: grpmax filtering AF 0.00107 (gnomAD v4.1) is about 11-fold above the <=0.0001 supporting threshold.

4

BA1, BS1, BS2 not met: highest ancestry frequency 0.00128 and zero homozygotes, far below stand-alone and strong benign cutoffs.

5

PS3 and BS3 not met: no functional splice or enzyme assay has been reported for this variant in either direction.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, a single supporting criterion (PP3) does not satisfy any pathogenic, likely pathogenic, benign or likely benign combination, and the variant is therefore classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Not met: PVS1 requires a null allele, but exon 14 skipping is in-frame (153 nt = 51 codons, no NMD) and the +2C>T change restores the consensus GT donor.	pvs1_generic_framework cspec final_classification_framework pvs1_variant_assessment pvs1_gene_context spliceai clinvar PMID:25741868 PMID:26467025
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: the case contains no proband and no parental genotype data, so a confirmed de novo occurrence cannot be evaluated.	cspec PMID:25741868 clinvar
PS3	Not met	Not met: no functional assay of MUTYH c.1476+2C>T exists, and submitters state functional studies remain unconfirmed.	cspec clinvar generic_acmg_combination_rules PMID:25741868 PMID:26467025 PMID:25186627
PS4	Not met	Not met: no case-control data exist for c.1476+2C>T, absent from all retrieved case literature yet present in gnomAD v4.1 (131/1,614,160 alleles).	clinvar cspec generic_acmg_combination_rules gnomad_v2 gnomad_v4 PMID:25186627 PMID:25741868
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Not met	Not met: grpmax filtering AF 0.00107 (~11x the <=0.0001 threshold) and African/African American AF 0.00128, despite v4.1's global AF of 0.0000812.	gnomad_v4 gnomad_v2 gnomad_canada cspec PMID:25741868
PM3	Not assessed	Not assessed: MUTYH is autosomal recessive and no data establish c.1476+2C>T in trans with a pathogenic MUTYH variant in any affected individual.	cspec clinvar PMID:25741868
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband, phenotype or parental information exists in this case, so an assumed de novo occurrence cannot be evaluated.	cspec PMID:25741868 clinvar
PP1	Not assessed	Not assessed: no pedigree, affected relatives or informative meioses for this variant exist in this case, so co-segregation cannot be counted.	cspec PMID:25741868 clinvar
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	Met	Met at supporting: SpliceAI max delta 0.257 exceeds the >=0.2 supporting cutoff but stays below the >=0.5 moderate threshold.	spliceai cspec generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history was provided, so phenotype specificity for MUTYH-associated polyposis could not be tested.	clinvar cspec generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar 187040 has zero expert-panel submissions among 17 (review status criteria provided, single submitter), so its expert-panel prerequisite fails.	clinvar cspec
BA1	Not met	Not met: the highest population frequency is 0.00128 (African/African American, gnomAD v4.1), roughly 40-fold below the >=0.05 BA1 stand-alone threshold.	gnomad_v4 gnomad_v2 cspec PMID:25741868
BS1	Not met	Not met: grpmax filtering AF 0.00107 (gnomAD v4.1) is ~10-fold below the >=0.01 threshold; a 4/132 1KG:LWK outlier was rejected as too small.	gnomad_v4 gnomad_v2 cspec PMID:25741868
BS2	Not met	Not met: zero homozygotes in gnomAD v4.1 (0/1,614,160 alleles) and v2.1 (0/282,888), although absence is expected at this allele frequency.	gnomad_v4 gnomad_v2 gnomad_canada cspec PMID:25741868
BS3	Not met	Not met: no functional assay demonstrates normal MUTYH function for c.1476+2C>T, as submitters confirm functional studies have not been reported.	cspec clinvar generic_acmg_combination_rules PMID:25741868
BS4	Not assessed	Not assessed: no pedigree or genotyped relatives exist to demonstrate non-segregation, so BS4 cannot be asserted.	cspec PMID:25741868 clinvar
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no evidence places c.1476+2C>T in cis with a pathogenic MUTYH variant, the only BP2 clause open to an autosomal-recessive gene.	cspec clinvar PMID:25741868
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.257 exceeds the <=0.1 supporting BP4 threshold for a splice-neutral effect.	spliceai cspec generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no case-level data show whether the variant occurred in a patient whose disease had an alternate molecular basis.	clinvar cspec generic_acmg_combination_rules
BP6	Not met	Not met: ClinVar 187040 has no expert-panel Benign/Likely benign assertion; its two Benign and two Likely benign submissions are ordinary laboratory assertions.	clinvar cspec
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001128425.2:c.1476+2C>T in MUTYH is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001121897.1:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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