Variant classification summary

NM_001128425.2:c.1258C>A

MUTYH · NP_001121897.1:p.(Leu420Met) · NM_001128425.2

GRCh37: chr1:45797157 G>T · GRCh38: chr1:45331485 G>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

BS3 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Leu420Met)

gnomAD AF

0.0005532145295322395 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BS3 supporting because p.L420M showed retained function in a controlled complementation assay.

2

VUS: one supporting benign criterion is insufficient for the generic Likely Benign combination rule.

3

VUS: no pathogenic or stand-alone benign combination rule is satisfied.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion does not satisfy Likely Benign, and no pathogenic or benign rule is satisfied, resulting in VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously established pathogenic Leu-to-Met comparator was documented for codon 420, and the reviewed assay classified p.L420M as functionally retained.	clinvar PMID:25820570
PS2	Not assessed	Not assessed: no documented proband de novo result with confirmed maternity and paternity, disease phenotype, and absent family history.	PMID:25741868
PS3	Not met	Not met: p.L420M was functionally retained, with mutation rate less than 1.7-fold above wild type in the MutY-deficient E. coli assay.	PMID:25820570
PS4	Not assessed	Not assessed: four reported colorectal-cancer cases lack the controls needed to calculate OR/RR >5.0 and a 95% CI excluding 1.0.	clinvar gnomad_v4 PMID:16774938
PM1	Not assessed	Not assessed: Cancer Hotspots found no significant MUTYH L420 hotspot, while no authoritative approved MUTYH domain list or qualifying domain boundary was available.	hotspots cspec
PM2	Not met	Not met: gnomAD v4.1 AF is 0.000553215, above the supplied PM2 supporting threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring phase evidence demonstrates c.1258C>A in trans with a pathogenic MUTYH variant.	clinvar cspec
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense variant at Leu420 was confirmed as pathogenic, and the documented PM5 search found zero same-residue candidates.	pm5_candidates PMID:25820570
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental genotype comparison is available for the proband.	PMID:25741868
PP1	Not assessed	Not assessed: no multiple affected relatives with informative genotypes and phenotype concordance are documented for co-segregation.	PMID:25741868
PP2	Not assessed	Not assessed: 47 MUTYH missense variants were assayed, but no validated low-benign-missense-rate metric was available to satisfy PP2.	PMID:25820570
PP3	Not met	Not met: REVEL 0.45 is below the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history details are available to establish a phenotype highly specific for a single genetic etiology.
PP5	Not met	Not met: ClinVar has zero exact-variant expert-panel submissions and no qualifying reputable pathogenic report; ordinary laboratory assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest qualifying grpmax FAF is 0.00152537, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest qualifying grpmax FAF is 0.00152537, below the generic BS1 threshold of 0.01 and without a gene-specific calculation exceeding it.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports up to two homozygotes, but does not establish healthy-adult status or full early-age penetrance required for BS2.	gnomad_v2 gnomad_v4 cspec PMID:25741868
BS3	Met	Met at supporting strength: p.L420M was functionally retained, with a mutation rate less than 1.7-fold above wild type in a controlled complementation assay.	PMID:25820570
BS4	Not assessed	Not assessed: no affected relatives without the variant, pedigree, or phenotype-verified non-segregation data are documented.	PMID:25741868
BP1	Not assessed	Not assessed: the available study evaluated 47 MUTYH missense variants but did not establish that disease is caused primarily by truncating variants.	PMID:25820570
BP2	Not assessed	Not assessed: no family or proband data establish c.1258C>A in trans with a pathogenic dominant allele or in cis with any pathogenic allele.	clinvar cspec
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.45 exceeds the generic BP4 supporting threshold of 0.29 and is therefore indeterminate for this missense variant.	revel
BP5	Not assessed	Not assessed: no qualifying case-level alternate molecular diagnosis or alternate pathogenic variant is documented for a carrier of this variant.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign assertion, and its ordinary benign or likely-benign submissions are excluded from BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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