NM_001048171.1:c.995C>T

MUTYH · NP_001041636.1:p.(Ser332Leu) · NM_001048171.1

GRCh37: chr1:45797482 G>A · GRCh38: chr1:45331810 G>A

Gene: MUTYH Transcript: NM_001048171.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MUTYH

Transcript

NM_001048171.1

Protein

NP_001041636.1:p.(Ser332Leu)

gnomAD AF

3.478641143379649e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001048171.1:c.995C>T (p.Ser332Leu) is a missense variant in exon 12 of MUTYH, a gene associated with autosomal recessive MUTYH-associated polyposis (MAP).

The variant is present at very low frequency in gnomAD (v2.1 AF=0.00512%; v4.1 AF=0.00348%), with no homozygous observations, consistent with PM2 supporting evidence.

Multiple in silico prediction tools concordantly predict a benign effect: REVEL score 0.116 (below 0.5 threshold), BayesDel score -0.476 (predicting benign), and SpliceAI predicts no splicing impact (max delta 0.00). This supports BP4 criteria.

ClinVar submissions predominantly classify this variant as Uncertain significance (7/11 submitters). One clinical laboratory (Ambry Genetics) classifies it as Likely benign. No expert panel classification has been issued.

Functional evidence from D'Agostino et al. 2009 (PMID:19092703) suggesting reduced glycosylase activity for p.S332L was identified through exploratory search but could not be independently verified as full-text was not available in the case materials. This evidence was not applied.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, placing this variant in the VUS (Variant of Uncertain Significance) category under generic ACMG/AMP 2015 combination rules.

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	NM_001048171.1:c.995C>T is a missense variant (p.Ser332Leu) and does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 decision tree does not apply to this variant class.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No established pathogenic variant at the same amino acid position (p.S332) with the same change (Ser332Leu) has been identified in ClinVar or the literature. PS1 requires an identical amino acid change in a known pathogenic variant.	clinvar pm5_candidates
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for this variant in ClinVar or the literature. MUTYH-associated polyposis is autosomal recessive, making de novo presentations unlikely to manifest phenotypically.	clinvar
PS3	Not assessed	The exploratory evidence pass identified a reference (D'Agostino et al. 2009, PMID:19092703) reporting reduced glycosylase activity for p.S332L. However, this paper was not retrieved as full-text in the case directory and could not be verified for variant-specific evidence. PS3 requires well-established functional data that can be independently confirmed.
PS4	Not met	No case-control study has demonstrated statistically significant enrichment of NM_001048171.1:c.995C>T in affected individuals versus controls. The variant is observed in gnomAD at low frequency, but population frequency alone does not establish case enrichment. MUTYH-associated polyposis is autosomal recessive, further complicating PS4 assessment for monoallelic observations.	gnomad_v2 gnomad_v4
PS5	Not met	No variant-specific functional study has established a damaging effect meeting PS5 criteria. The variant has not been classified as pathogenic by any expert panel or multiple submitters with concordant criteria.	clinvar
PM1	Not assessed	Ser332 lies within the MUTYH C-terminal domain (approximately residues 301-490), a region implicated in PCNA binding and protein interactions. However, the MUTYH VCEP (ClinGen InSiGHT v1.0.0) does not provide an explicit PM1 domain definition or mutational hot spot specification for generic adjudication. Without VCEP-defined critical domain boundaries, PM1 cannot be applied under current framework rules.	cspec
PM2	Met	NM_001048171.1:c.995C>T is present at very low frequency in population databases. gnomAD v2.1 reports 14 heterozygotes among 273,222 alleles (AF=0.00512%, 0 homozygotes); gnomAD v4.1 reports 56 heterozygotes among 1,609,824 alleles (AF=0.00348%, 0 homozygotes). Both allele frequencies are below the 0.1% PM2 threshold. The variant is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same residue (p.Ser332) with a different amino acid change has been identified. The PM5 candidate harvest found zero same-residue comparator candidates meeting the governing PM5 rule.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmed paternity/maternity) has been reported for this variant. MUTYH-associated polyposis is autosomal recessive; PM6 is rarely applicable in recessive cancer predisposition genes.	clinvar
PP1	Not met	No cosegregation data are available for NM_001048171.1:c.995C>T. No family-based segregation study including this variant has been published or is recorded in major databases.
PP2	Not met	While MUTYH is a gene in which missense variants are a known disease mechanism for MUTYH-associated polyposis, PP2 under generic ACMG/AMP 2015 requires that the gene have a low rate of benign missense variation. MUTYH tolerates missense variation in the general population (numerous missense variants with AF>0.1% in gnomAD), precluding application of PP2.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple in silico prediction tools suggest a benign impact of this missense change. REVEL score is 0.116 (below the 0.5 threshold), BayesDel score is -0.476 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta score = 0.00). No computational tool supports a deleterious effect, so PP3 is not met.	revel bayesdel spliceai
PP4	Not assessed	No detailed phenotype or family history information specific to the proband was available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene.
PP5	Not met	No reputable source has classified NM_001048171.1:c.995C>T as pathogenic. ClinVar aggregates 11 submissions: 7 classify as Uncertain significance, 1 as Likely benign, and 3 as not provided or not classified. No expert panel has issued a classification.	clinvar
BA1	Not met	The variant allele frequency is substantially below the BA1 threshold of 1%. gnomAD v2.1 reports AF=0.00512% and gnomAD v4.1 reports AF=0.00348%. The variant is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency is below the BS1 threshold of 0.3%. gnomAD v2.1 reports AF=0.00512% and gnomAD v4.1 reports AF=0.00348%. The highest subpopulation frequency (South Asian, AF=0.045%) also falls below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of NM_001048171.1:c.995C>T are reported in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes) or any other population database. BS2 requires observation in a homozygous state in healthy adults without disease manifestation.	gnomad_v2 gnomad_v4
BS3	Not met	The only functional evidence identified (D'Agostino et al. 2009, PMID:19092703, unverified) reports reduced glycosylase activity for p.S332L, which would indicate a damaging rather than benign effect. BS3 requires well-established functional studies showing no damaging effect on protein function or splicing.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. No published family has been identified in which unaffected family members carry NM_001048171.1:c.995C>T in trans with a pathogenic MUTYH variant without developing MUTYH-associated polyposis.
BP1	N/A	MUTYH-associated polyposis can be caused by both truncating and missense variants. BP1 applies only when a gene's disease mechanism is exclusively through protein truncation.
BP2	Not met	No evidence demonstrates that NM_001048171.1:c.995C>T occurs in cis with a known pathogenic MUTYH variant in an individual with disease. Phase information is not available from ClinVar or the literature.
BP4	Met	Multiple lines of computational evidence suggest that this missense variant has no impact on gene product function. The REVEL score is 0.116 (below 0.5), BayesDel score is -0.476 (predicting benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three in silico tools concordantly predict a benign effect.	revel bayesdel spliceai
BP5	Not assessed	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No proband-level genetic workup showing an alternative cause (e.g., biallelic pathogenic APC variants in a polyposis case) was available in the case materials.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar submissions predominantly classify it as Uncertain significance (7 submitters), with one Likely benign classification (Ambry Genetics, single submitter, criteria provided). A single Likely benign call from one laboratory does not meet the threshold for BP6.	clinvar
BP7	N/A	NM_001048171.1:c.995C>T is a missense variant (p.Ser332Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing prediction algorithms predict no impact on the splice consensus sequence.
BP3	N/A	Skipped per instruction: BP3 applies to in-frame insertions/deletions; this variant is a single-nucleotide substitution.
PM3	N/A	Skipped per instruction: PM3 assessment deferred; no verified trans observations with a pathogenic variant available in case materials.
PM4	N/A	Skipped per instruction: PM4 applies to protein-length changing variants (in-frame indels, stop-loss); this variant is a single-nucleotide substitution.

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