NM_001128425.2:c.1255G>A

MUTYH · NP_001121897.1:p.(Ala419Thr) · NM_001128425.2

GRCh37: chr1:45797160 C>T · GRCh38: chr1:45331488 C>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Ala419Thr)

gnomAD AF

8.735745555612005e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is a missense substitution (NM_001128425.2:c.1255G>A, p.Ala419Thr) in exon 13 of MUTYH.

The variant is present at very low frequency in gnomAD v2.1 (AF=0.00672%, 19/282,560 alleles, 0 homozygotes) and v4.1 (AF=0.00874%, 141/1,614,058 alleles, 1 homozygote), and is absent from gnomAD-Canada, meeting PM2 at the supporting level.

Multiple in silico tools predict no damaging effect: REVEL score 0.414 (below the 0.5 pathogenic threshold), BayesDel score -0.184886 (benign-leaning), and SpliceAI delta score 0.00 (no predicted splice impact), meeting BP4 at the supporting level.

No functional studies, segregation data, de novo observations, or variant-specific literature have been identified for this variant. The MUTYH VCEP (InSiGHT Hereditary Colorectal Cancer/Polyposis Specification v1.0.0) framework was present but incomplete with no gene-specific criteria rules; generic ACMG/AMP 2015 criteria were applied.

In ClinVar, the variant is reported as Uncertain significance by 11 of 14 submitters. Ambry Genetics classifies as Benign and Labcorp/Invitae as Likely benign, though the underlying evidence is not publicly accessible. The single homozygote in gnomAD v4.1 warrants attention for a recessive disorder but lacks phenotype data.

The only applicable criteria are PM2_supporting (pathogenic supporting) and BP4_supporting (benign supporting). These oppose each other, resulting in conflicting evidence insufficient to classify beyond Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so 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	This is a missense variant (c.1255G>A, p.Ala419Thr); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon-level deletions). The variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 framework (PMC6185798).	pvs1_variant_assessment
PS1	Not met	No evidence that the same amino acid change (p.Ala419Thr) has been established as pathogenic in a different nucleotide change in MUTYH.
PS2	Not met	No de novo observation reported for this variant. No parentage-confirmed de novo data available in ClinVar submissions or published literature.
PS3	Not met	No variant-specific functional studies have been reported. ClinVar submitters explicitly state 'functional studies have not been reported for this variant.' OncoKB did not identify variant-specific functional evidence. In silico scores (REVEL 0.414, BayesDel -0.185) are computational predictions, not functional assay data.	gnomad_v2 clinvar oncokb revel bayesdel
PS4	Not met	The variant is present in gnomAD at low frequency (v2.1: AF=0.0067%, 19/282,560; v4.1: AF=0.0087%, 141/1,614,058 with 1 homozygote), which argues against significant enrichment in affected individuals. No case-control study demonstrating statistically significant enrichment in affected vs. controls has been identified. While the variant has been observed in individuals with colorectal cancer and suspected Lynch syndrome per ClinVar reports, the population frequency and lack of controlled association data do not meet PS4.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PS5	Not met	PS5 requires data from a well-established assay showing a damaging effect, supported by strong in silico data. No variant-specific functional assay evidence exists, and in silico predictions are mixed to benign-leaning (REVEL 0.414, BayesDel -0.185).
PM1	Not met	This variant is located at residue 419 (p.Ala419Thr), which does not lie in a statistically significant somatic or germline hotspot. The hotspot analysis confirms the variant is not in a known functional domain cluster with excess pathogenic variation.
PM2	Met	This variant is absent from gnomAD-Canada and present at very low frequency in gnomAD v2.1 (AF=0.00672%, 19/282,560 alleles, 0 homozygotes) and v4.1 (AF=0.00874%, 141/1,614,058 alleles, 1 homozygote). Both frequencies are well below the 0.1% PM2 threshold. The single homozygote in v4.1 is noted but does not negate PM2 at the supporting level given the overall rarity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants identified. PM5 candidate harvesting could not confirm classic same-residue pathogenic comparator semantics (different amino acid change at p.Ala419 with established pathogenicity).	pm5_candidates
PM6	Not met	No de novo observation reported for this variant. No parentage-confirmed data available.
PP1	Not met	No segregation data available. No family studies demonstrating cosegregation of this variant with disease phenotype have been identified.
PP2	Not met	PP2 applies to genes where missense variants are a well-established mechanism of disease and the gene has a low rate of benign missense variation. MUTYH-associated polyposis is caused by both missense and truncating variants, but MUTYH also has a substantial number of rare missense variants in the general population. The variant does not meet PP2 without gene-level calibration of benign missense constraint.
PP3	Not met	In silico predictions are mixed and do not support a deleterious effect. REVEL score is 0.414 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.184886 (benign-leaning; negative values indicate benign prediction). SpliceAI predicts no splice impact (max delta = 0.00). Multiple ClinVar submitters note that in silico tools predict a benign effect (e.g., 'three of five in-silico tools predict a benign effect'). The weight of computational evidence favors a benign interpretation, supporting BP4 rather than PP3.	revel bayesdel spliceai
PP4	Not met	PP4 requires a highly specific phenotype or family history consistent with a single genetic etiology. While MUTYH variants are associated with colorectal polyposis/cancer, the phenotype is not sufficiently specific (overlaps with FAP, AFAP, Lynch syndrome, and sporadic CRC). The variant has been reported in individuals with diverse phenotypes including colorectal cancer, suspected Lynch syndrome, and breast cancer, further reducing phenotypic specificity.	clinvar
PP5	Not met	PP5 requires that a reputable source (e.g., expert clinical laboratory with strong reputation) has recently classified the variant as pathogenic/likely pathogenic with supporting evidence not available to this assessment. The majority of ClinVar submitters classify this as Uncertain significance (11 of 14). One submitter (Ambry Genetics) classifies as Benign and one (Labcorp/Invitae) as Likely benign. No reputable source has classified this as pathogenic. The preponderance of clinical opinion is VUS or benign-leaning.	clinvar
BA1	Not met	The variant frequency in gnomAD is well below the 1% BA1 threshold (v2.1: AF=0.0067%; v4.1: AF=0.0087%).	gnomad_v2 gnomad_v4
BS1	Not met	The variant frequency in gnomAD is below the 0.3% BS1 threshold (v2.1: AF=0.0067%; v4.1: AF=0.0087%). The presence of 1 homozygote in v4.1 is noted but does not elevate the allele frequency above 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult homozygous for a recessive disorder with full penetrance expected at an early age. While 1 homozygote is observed in gnomAD v4.1, the phenotype of this individual is unknown. Without confirmation that this individual is a healthy adult, BS2 cannot be applied. Additionally, MUTYH-associated polyposis has variable expressivity and age-dependent penetrance, complicating the application of BS2 without detailed phenotype data.	gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No variant-specific functional studies have been performed. In silico predictions (REVEL 0.414, BayesDel -0.185) are computational only and do not constitute functional assay evidence under BS3.	clinvar revel bayesdel
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease. No family studies involving this variant have been identified.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. MUTYH-associated polyposis is caused by both missense (e.g., Y165C, G382D) and truncating pathogenic variants. Multiple MUTYH missense variants have established pathogenicity with functional validation, so BP1 does not apply.	PMID:17161978
BP2	Not met	BP2 requires observation in trans with a known pathogenic variant or in cis with a pathogenic variant in a dominant disorder in a healthy individual. No such observation has been reported for this variant.
BP4	Met	Multiple lines of computational evidence suggest this variant does not impact protein function. REVEL score is 0.414 (below the 0.5 pathogenic threshold). BayesDel score is -0.184886 (negative scores indicate benign prediction). SpliceAI predicts no splice impact (max delta = 0.00). ClinVar submitters note that multiple in silico tools predict a benign effect (e.g., 'three of five in-silico tools predict a benign effect'; 'computational prediction suggests that this variant may not impact protein structure and function'). The convergent in silico evidence supports BP4.	revel bayesdel spliceai clinvar
BP5	Not met	BP5 requires that the variant be found in a case with an alternate molecular basis for disease (e.g., a second pathogenic variant in another gene explaining the phenotype). No such data available.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign/likely benign with evidence not available to this assessment. While Ambry Genetics (a reputable clinical laboratory) classifies this variant as Benign and Labcorp/Invitae classifies as Likely benign, the evidence underlying these classifications is not accessible for verification. The majority of submitters (11 of 14) classify as VUS. Without access to the internal data supporting the Benign/Likely benign classifications, BP6 is not met.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant is a missense substitution (c.1255G>A, p.Ala419Thr), not a synonymous variant. BP7 is therefore not applicable.
BP3	N/A	Skipped per adjudication instructions — trivially not applicable (in-frame indel criterion, variant is a substitution).
PM3	N/A	Skipped per adjudication instructions — trivially not applicable (requires recessive disorder with second pathogenic allele in trans; not on assess list).
PM4	N/A	Skipped per adjudication instructions — trivially not applicable (protein length change criterion; variant is a substitution).

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