Variant classification summary

NM_001048174.2:c.137A>C

MUTYH · NP_001041639.1:p.(Glu46Ala) · NM_001048174.2

GRCh37: chr1:45799212 T>G · GRCh38: chr1:45333540 T>G

Gene: MUTYH Transcript: NM_001048174.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MUTYH

Transcript

NM_001048174.2

Protein

NP_001041639.1:p.(Glu46Ala)

gnomAD AF

2.4782901780403664e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is 2.47829e-06, below 0.0001, with zero homozygotes.

2

BP4 supporting: REVEL score 0.023 is at or below the 0.29 supporting threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting pathogenic criterion and one supporting benign criterion satisfy neither a pathogenic nor a benign combination, so the call is 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 validated pathogenic comparator producing the same Glu46Ala amino-acid change is documented.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no affected-proband phenotype, parental genotypes, confirmation of both maternity and paternity, or family-history information is available.
PS3	Not assessed	Not assessed: no variant-specific in vitro or in vivo assay, validated controls, reproducibility data, or quantitative functional result was reported for c.137A>C (p.Glu46Ala).	PMID:25741868 PMID:24310308
PS4	Not assessed	Not assessed: gnomAD reports 4/1,614,016 alleles, but no affected-case count exists to calculate the required OR >5.0 with a 95% CI excluding 1.0.	gnomad_v4
PM1	Not met	Not met: MUTYH E46 has no supplied approved critical-domain definition or statistically significant Cancer Hotspots result.	cspec hotspots
PM2	Met	Met at supporting: gnomAD v4.1 AF is 2.47829e-06, below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 cspec PMID:25741868
PM3	Not assessed	Not assessed: no parent/offspring testing or other phase evidence establishes whether c.137A>C is in trans with a pathogenic MUTYH variant.	cspec PMID:24310308 PMID:25452455 PMID:27854360
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 pathogenic missense variant at MUTYH residue 46 is documented in the available evidence.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no affected-proband phenotype or evidence of assumed de novo occurrence without confirmed maternity and paternity is available.
PP1	Not assessed	Not assessed: no affected family members, informative meioses, or variant-positive relatives are reported for co-segregation analysis.
PP2	Not assessed	Not assessed: gene-level benign-missense constraint and a common MUTYH missense disease mechanism are not established by the supplied data.
PP3	Not met	Not met: missense REVEL score 0.023 is below the PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to determine whether the presentation is highly specific for a single genetic etiology.
PP5	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions and no reviewed publication reports NM_001048174.2:c.137A>C as pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.9e-07, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 clinvar PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.9e-07, below the generic BS1 default of 0.01 and not suggestive of excess frequency.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v2.1 non-cancer exomes and v4.1 each report zero homozygotes, with no qualifying healthy-adult homozygous observation.	gnomad_v2 gnomad_v4 cspec
BS3	Not assessed	Not assessed: no variant-specific assay demonstrated preserved MUTYH protein function or normal splicing with validated controls and a quantitative result for c.137A>C (p.Glu46Ala).	PMID:25741868 PMID:24310308
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: loss-of-function relevance is documented, but a primarily truncating MUTYH disease spectrum is not established.
BP2	Not assessed	Not assessed: the case provides no verified cis or trans phase result with a pathogenic variant.
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	Met	Met at supporting: missense REVEL score 0.023 is at or below the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no alternate molecular basis for the patient's disease is documented, so BP5 cannot be evaluated.
BP6	Not met	Not met: the only benign assertion is one ordinary laboratory submission, while the exact ClinVar record has 0 expert-panel submissions and conflicting classifications.	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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