Variant classification summary

NM_001128425.2:c.1585C>A

MUTYH · NP_001121897.1:p.(Leu529Met) · NM_001128425.2

GRCh37: chr1:45795043 G>T · GRCh38: chr1:45329371 G>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

Likely Benign

BS1 strong BS3 supporting BP4 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Leu529Met)

gnomAD AF

0.0031567932919026307 (v2.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 strong is supported by the 0.0241 ancestry-specific gnomAD allele frequency.

2

Likely Benign: BS3 supporting is supported by retained function in a quantitative MUTYH complementation assay.

3

Likely Benign: BP4 supporting is supported by REVEL 0.237 below the <=0.29 threshold.

Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Likely Benign when one strong benign criterion is combined with at least one supporting benign criterion; BS1 strong plus BS3 and BP4 supporting satisfy this rule.

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	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001128425.2:c.1585C>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Leu529Met). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1'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
PS1	Not met	Not met: the only p.Leu529Met functional report tested the index variant itself and found it functionally retained, with no independent same-amino-acid comparator.	PMID:25820570
PS2	Not assessed	Not assessed: no confirmed de novo observation or parental testing is documented for c.1585C>A.	cspec
PS3	Not met	Not met: p.Leu529Met was functionally retained in a MutY-deficient E. coli assay, remaining below the predefined 1.7-fold wild-type mutation-rate threshold for impairment.	cspec PMID:25820570
PS4	Not assessed	Not assessed: no exact-variant affected-case count, control comparison, odds ratio, or enrichment threshold is available.	cspec PMID:22703879 PMID:24728327
PM1	Not assessed	Not assessed: the applicable MUTYH specification provides no authoritative domain table or complete critical-domain boundaries for checking residue 529.	cspec
PM2	Not met	Not met: non-cancer gnomAD frequencies of 0.00363 and 0.00155 exceed the generic PM2 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation or validated pathogenic MUTYH allele in trans is documented for this autosomal-recessive condition.	cspec
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.1585C>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Leu529Met). 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	Not assessed	Not assessed: no independent pathogenic or likely pathogenic missense comparator at MUTYH residue 529 was identified for p.Leu529Met.	PMID:25820570
PM6	Not assessed	Not assessed: no apparently de novo proband report without parental testing is documented for c.1585C>A.	cspec
PP1	Not assessed	Not assessed: zero informative family members or meioses are documented for segregation of c.1585C>A.	cspec
PP2	Not met	Not met: MUTYH has numerous missense variants and established recurrent missense disease variants, so the PP2 low-benign-missense pattern is not demonstrated.	PMID:25820570 cspec
PP3	Not met	Not met: REVEL 0.237 is below the >=0.644 supporting PP3 threshold for missense variants.	cspec revel
PP4	Not assessed	Not assessed: no exact-variant patient phenotype or phenotype-specific diagnostic context is available for PP4.	cspec
PP5	Not met	Not met: ClinVar records 0 expert-panel submissions, and the available exact-variant submissions are Benign or Likely benign.	clinvar
BA1	Not met	Not met: the highest observed allele frequency was 0.0241, below the generic BA1 threshold of 0.05.	cspec gnomad_v2 gnomad_v4 PMID:25741868
BS1	Met	Met, strong: gnomAD v2.1 non-cancer Admixed American AF 0.0241 exceeds the generic BS1 threshold of 0.01.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: 16 non-cancer gnomAD homozygotes are reported, but age and unaffected clinical status needed for BS2 are not documented.	cspec gnomad_v2 gnomad_v4
BS3	Met	Met at supporting: p.Leu529Met was functionally retained in a quantitative MutY-deficient E. coli assay using a less-than-1.7-fold wild-type mutation-rate retention threshold.	cspec PMID:25820570
BS4	Not assessed	Not assessed: no affected relatives lacking c.1585C>A or other documented non-segregation evidence is reported.	cspec
BP1	Not met	Not met: documented recurrent MUTYH missense variants mean its disease mechanism is not established as truncating-only for BP1.	PMID:25820570 cspec
BP2	Not assessed	Not assessed: no validated pathogenic co-allele or cis/trans phase information is documented for c.1585C>A.	cspec gnomad_v2
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.1585C>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Leu529Met). 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	Met	Met at supporting: REVEL 0.237 is within the <=0.29 supporting BP4 threshold for missense variants.	cspec revel
BP5	Not assessed	Not assessed: no affected individual has a documented alternate molecular explanation that would satisfy BP5.
BP6	Not met	Not met: exact-variant ClinVar has 0 expert-panel submissions, so its Benign/Likely benign laboratory labels cannot trigger BP6.	clinvar
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.1585C>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Leu529Met). 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

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.