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.1 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.2 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.3 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.4
MUTYH
Final classification
VUS
MUTYH c.995C>T · p.Ser332Leu
MUTYH
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).
InSiGHT Hereditary Colorectal Cancer/Polyposis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MUTYH c.995C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_001048171.1 · variants mapped to exon structure
MUTYH
NM_001048171.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF=0.00512% (14/273222 alleles0 homozygotes).
✓
BP4
supporting
Benign
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: 0.116 (benignbelow 0.5 threshold).BayesDel: -0.475899 (negative score
Assessed · not applied
Pathogenic
PS1
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.
PS2
No de novo observation with confirmed paternity and maternity has been reported for this variant in ClinVar or the literature.
PS3
The exploratory evidence pass identified a reference (D'Agostino et al.
PS4
No case-control study has demonstrated statistically significant enrichment of NM_001048171.1:c.995C>T in affected individuals versus controls.
PM1
Ser332 lies within the MUTYH C-terminal domain (approximately residues 301-490), a region implicated in PCNA binding and protein interactions.
PM5
No pathogenic missense variant at the same residue (p.Ser332) with a different amino acid change has been identified.
PM6
No assumed de novo observation (without confirmed paternity/maternity) has been reported for this variant.
PP1
No cosegregation data are available for NM_001048171.1:c.995C>T.
PP2
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.
PP3
Multiple in silico prediction tools suggest a benign impact of this missense change.
PP4
No detailed phenotype or family history information specific to the proband was available in the case materials.
PP5
No reputable source has classified NM_001048171.1:c.995C>T as pathogenic.
Benign
BA1
The variant allele frequency is substantially below the BA1 threshold of 1%.
BS1
The variant allele frequency is below the BS1 threshold of 0.3%.
BS2
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.
BS3
The only functional evidence identified (D'Agostino et al.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP2
No evidence demonstrates that NM_001048171.1:c.995C>T occurs in cis with a known pathogenic MUTYH variant in an individual with disease.
BP5
BP5 applies when a variant is found in a case with an alternate molecular basis for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.47864e-05; MAF= 0.00348%, 56/1609824 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000451821; MAF= 0.04518%, 41/90744 alleles, homozygotes = 0); grpmax FAF= 0.00034176.
v2.1
This variant is present in gnomAD v2.1 (AF= 5.12404e-05; MAF= 0.00512%, 14/273222 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000365764; MAF= 0.03658%, 11/30074 alleles, homozygotes = 0); grpmax FAF= 0.00020417.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0035%
· 56 / 1,609,824
0 hom · FAF 0.034%
0 hom · FAF 0.034%
South Asian 41 / 90,744 |
0.045% |
East Asian 3 / 44,724 |
0.0067% |
Admixed American 1 / 59,414 |
0.0017% |
European (non-Finnish) 11 / 1,177,952 |
0.00093% |
+ 6 not observed (Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0051%
· 14 / 273,222
0 hom · FAF 0.02%
0 hom · FAF 0.02%
South Asian 11 / 30,074 |
0.037% |
East Asian 2 / 19,416 |
0.01% |
Admixed American 1 / 34,558 |
0.0029% |
+ 5 not observed (African/African American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.116. BayesDel score = -0.475899.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MUTYH, a DNA glycosylase, is frequently mutated in colorectal cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25645574 ↗
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
24310308 ↗
ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).
CLINVAR
24728327 ↗
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR