Variant classification summary

NM_001128425.2:c.714C>T

MUTYH · NP_001121897.1:p.(Asn238=) · NM_001128425.2

GRCh37: chr1:45798137 G>A · GRCh38: chr1:45332465 G>A

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

PM2 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Asn238=)

gnomAD AF

4.337083051422935e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because the gnomAD v4.1 allele frequency is 4.33708e-05, below the 0.0001 threshold, with zero homozygotes.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting criterion alone satisfies no pathogenic, likely pathogenic, benign, or likely 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 synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband disease, family-history, or confirmed maternity-and-paternity evidence is available for this variant.	PMID:16134147
PS3	Not assessed	Not assessed: no variant-specific validated functional assay was identified for synonymous MUTYH c.714C>T (p.Asn238=).	PMID:16134147
PS4	Not assessed	Not assessed: no variant-specific case-control odds ratio or relative risk, and no confidence interval, is available to evaluate the >5.0 and non-inclusion-of-1.0 thresholds.	PMID:16134147
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: gnomAD v4.1 AF 4.33708e-05 is below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
PM3	Not assessed	Not assessed: no documented parent/offspring phasing or affected-proband observation places c.714C>T in trans with a pathogenic variant.	clinvar PMID:16134147
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo observation or parental testing is documented for the evaluated variant.	PMID:16134147
PP1	Not assessed	Not assessed: no affected relatives or informative segregation data are documented for the evaluated variant.	PMID:16134147
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PP3	Not met	Not met: synonymous-variant SpliceAI max delta 0.114 is below the PP3 supporting threshold of >= 0.2.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to establish a highly specific presentation for a single-gene disease.
PP5	Not met	Not met: ClinVar has 0 expert-panel submissions for the exact variant, and available laboratory assertions are not eligible to trigger PP5.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.00049456, far below the BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency is 0.00049456, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS2	Not met	Not met: zero homozygotes are reported across the available gnomAD datasets, so no qualifying healthy adult homozygote is observed.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS3	Not assessed	Not assessed: no variant-specific validated functional assay demonstrated no damaging effect for synonymous MUTYH c.714C>T (p.Asn238=).	PMID:16134147
BS4	Not assessed	Not assessed: no tested affected relatives are documented, so lack of segregation cannot be evaluated.	PMID:16134147
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented cis or trans co-occurrence with a pathogenic variant is available for c.714C>T.	clinvar PMID:16134147
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: synonymous-variant SpliceAI max delta 0.114 exceeds the BP4 supporting threshold of <= 0.1.	spliceai
BP5	Not assessed	Not assessed: no case-level evidence links this variant to a patient with an independently established alternate molecular basis for disease.
BP6	Not met	Not met: ClinVar has 0 expert-panel submissions, so its ordinary laboratory Likely benign and Benign assertions cannot trigger BP6.	clinvar
BP7	Not met	Not met: synonymous variant SpliceAI max delta 0.114 exceeds the <= 0.1 no-impact cutoff required for BP7.	spliceai

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.