NM_001128425.2:c.925C>T

MUTYH · NP_001121897.1:p.(Arg309Cys) · NM_001128425.2

GRCh37: chr1:45797846 G>A · GRCh38: chr1:45332174 G>A

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

PS3 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Arg309Cys)

gnomAD AF

0.0006944599319540776 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PS3 (Supporting): in an E. coli complementation assay the mutation rate was 2.9-fold above wild type, indicating partially defective MUTYH function.

Overall: VUS - a single supporting pathogenic criterion does not reach the ACMG/AMP Likely Pathogenic or Pathogenic thresholds.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, a single supporting pathogenic criterion matches no Pathogenic or Likely Pathogenic combination, and with no qualifying benign combination the variant is 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	N/A	Not applicable: p.Arg309Cys is a missense substitution, so the null-variant classes PVS1 requires are not present.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic substitution at the same residue, Arg309, was available as a comparator.	cspec PMID:19032956 PMID:25820570 PMID:22297469
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parentage was documented for p.Arg309Cys.	cspec
PS3	Met	Met (Supporting): in an E. coli complementation assay the mutation rate was 2.9-fold above wild type, indicating partially defective MUTYH function.	cspec PMID:25820570 PMID:22297469
PS4	Not assessed	Not assessed: no case-control enrichment for MUTYH-associated polyposis was available for this variant.	cspec PMID:19032956 PMID:25820570 PMID:22297469
PM1	Not assessed	Not assessed: no complete MUTYH critical-domain map was available to determine whether residue 309 lies in a hotspot.	cspec
PM2	Not met	Not met: gnomAD v4.1 reports 1,121 alternate alleles including one homozygote, so the variant is not absent from population data.	gnomad_v4 gnomad_v2 PMID:22297469 PMID:19032956 cspec
PM3	Not assessed	Not assessed: no affected individual with a pathogenic MUTYH variant confirmed in trans was documented.	cspec PMID:19032956 PMID:25820570 PMID:16557584
PM4	N/A	Not applicable: a missense substitution does not change protein length, which is what PM4 evaluates.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no other pathogenic missense variant at Arg309 was identified as a comparator.	cspec PMID:19032956 PMID:25820570 PMID:22297469
PM6	Not assessed	Not assessed: no presumed de novo occurrence with parental testing was reported for p.Arg309Cys.	cspec PMID:19032956 PMID:22297469 PMID:25820570
PP1	Not assessed	Not assessed: no informative segregation data with affected and unaffected relatives were available.	cspec PMID:19032956 PMID:22297469 PMID:25820570
PP2	Not assessed	Not assessed: missense variation was not established as a common MUTYH disease mechanism with a low benign missense rate.	cspec PMID:16557584 PMID:26377631 PMID:25741868
PP3	Not met	Not met: REVEL 0.592 falls within the 0.250-0.750 gray zone, so computational evidence does not support pathogenicity.	cspec revel
PP4	Not assessed	Not assessed: no phenotype or clinical findings for the affected individual were available to evaluate MUTYH-associated polyposis specificity.	cspec
PP5	Not met	Not met: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion was found.	clinvar
BA1	Not met	Not met: gnomAD v4.1 overall allele frequency is 0.0695%, far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: the highest gnomAD v4.1 population frequency is 0.0883% (non-Finnish Europeans), below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 PMID:22297469 cspec
BS2	Not assessed	Not assessed: the single gnomAD homozygote has no documented healthy-adult phenotype, so BS2 cannot be applied.	gnomad_v4 gnomad_v2 cspec
BS3	Not met	Not met: the direct E. coli complementation assay showed partially defective function rather than the normal function BS3 requires.	PMID:25820570 PMID:22297469
BS4	Not assessed	Not assessed: no documented unaffected carrier relative or family non-segregation data were available.	cspec PMID:19032956 PMID:22297469 PMID:25820570
BP1	Not assessed	Not assessed: missense variation is not established as generally benign in MUTYH, and no BP1 rule was supplied.	cspec PMID:16557584 PMID:26377631 PMID:25820570
BP2	Not assessed	Not assessed: no phase-resolved observation of p.Arg309Cys alongside a pathogenic MUTYH variant was documented.	cspec PMID:19032956 PMID:22297469 PMID:25820570
BP3	N/A	Not applicable: a missense substitution does not alter protein length within a repetitive region, which is what BP3 requires.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.592 falls within the 0.250-0.750 gray zone, so computational evidence does not support a benign call.	cspec revel
BP5	Not assessed	Not assessed: no individual-level phenotype or alternative molecular cause was available to evaluate BP5.	cspec
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign assertion was found.	clinvar
BP7	N/A	Not applicable: the variant is missense and alters the protein sequence, so the silent-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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