Final classification

Likely Benign

BS1BS3BP4

MUTYH

c.74G>A

p.Gly25Asp

missense · exon 2

Gene context NCBI Gene ↗ OncoKB ↗

MUTYH encodes a DNA repair enzyme (a glycosylase) that fixes oxidative DNA damage by removing adenine bases that have been mistakenly paired with guanine or with oxidized guanine lesions. Inherited mutations in both copies of the gene cause MUTYH-associated polyposis (MAP), a recessive condition that strongly predisposes people to multiple colorectal polyps and colorectal cancer. The gene acts as a tumor suppressor whose loss of function allows DNA damage to accumulate, and somatic changes in it have also been reported in colon cancer, though whether they drive cancer on their own is not fully established.

This variant

MUTYH encodes a DNA-repair glycosylase, and biallelic loss-of-function causes autosomal-recessive MUTYH-associated polyposis with colorectal cancer predisposition.

Transcript

NM_001128425.2

HGVS · transcript:coding

NM_001128425.2:c.74G>A

GRCh38

chr1:45334474 C>T

GRCh37

chr1:45800146 C>T

Likely Benign: BS1 (strong), BS3 (supporting), and BP4 (supporting) satisfy the generic ACMG/AMP benign combination rule.

Classification rationale

BS1BS3BP4 Likely Benign

MUTYH c.74G>A missense · exon 2

Likely Benign: BS1 strong because the East Asian allele frequency exceeds 1%. Likely Benign: BS3 supporting because p.Gly25Asp was functionally retained in controlled complementation testing. Likely Benign: BP4 supporting because REVEL 0.111 is below the benign computational threshold.

BS1 + BS3 + BP4 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001128425.2 · variants mapped to exon structure

MUTYH NM_001128425.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

Met at strong: the East Asian gnomAD v2.1 frequency is 1.30313%, exceeding the generic BS1 threshold of 1%.

The InSiGHT MUTYH specification is identified, but its retrieved ruleset has no structured BS1 population threshold; the supplied generic ACMG/ClinGen threshold is therefore used.gnomAD v2.1 reports the highest East Asian AF as 0.0130313 (260/19952), while gnomAD v4.1 reports 0.0113403 (509/44884); both exceed 0.01.The all-comers AF is lower in both datasets: 0.00105347 in gnomAD v2.1 and 0.000441106 in gnomAD v4.1, demonstrating that ancestry-specific frequency is decisive here.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗PMID:17703316 ↗PMID:18811933 ↗

BS3 supporting Benign

Met at supporting: p.G25D was functionally retained in a controlled BER complementation assay below the 1.7-fold defect threshold relative to wild type.

Komine et al. evaluated 47 MUTYH variants in a MutY-deficient E. coli BER complementation assay, with rifampicin-resistant mutation rate as the functional readout, nine independent overnight cultures, an empty-vector negative control, and wild-type MUTYH comparator.The published calibration categorized mutation rates less than 1.7-fold above wild type as functionally retained; p.G25D was explicitly categorized as functionally retained.The study also reported minimal differences in protein expression among tested variants and nuclear localization of the tested nuclear isoform, providing assay-context controls, but these measures do not replace the BER readout.

PMID:25820570 ↗PMID:18811933 ↗

BP4 supporting Benign

Met, supporting: REVEL 0.111 is below the <=0.29 BP4 supporting threshold for this missense variant.

The MUTYH InSiGHT VCEP framework was checked first; its available ruleset contains no specific BP4 assignment, so the supplied generic calibration applies.The variant consequence is missense, so REVEL is the sole applicable computational path; SpliceAI is not used for BP4.REVEL score: 0.111. The supplied ClinGen SVI calibration sets BP4 supporting at <=0.29 (Pejaver et al. 2022, PMID:36413997).

cspec ↗

Assessed · not applied · 13 not met · 8 not assessed

Pathogenic

PS1 Not met: MUTYH p.Gly25Asp is reported, but no reliable pathogenic classification establishes the same amino-acid change as a PS1 comparator.

PS2 Not assessed: no proband-parent genotypes or confirmed de novo occurrence are documented for p.Gly25Asp.

PS3 Not met: p.G25D was functionally retained in complementation testing, with a mutation rate below the study's 1.7-fold defect threshold relative to wild type.

PS4 Not met: the reported 6/138 versus 3/343 enrichment concerned a linked c.53C>T/c.74G>A haplotype, not isolated c.74G>A.

PM1 Not met: residue 25 is not supported by an approved MUTYH critical-domain entry or a statistically significant hotspot in the available specification materials.

PM2 Not met: the gnomAD v4.1 all-comers frequency is 0.000441106, above the PM2 threshold of 0.0001.

PM3 Not assessed: one affected patient had four heterozygous MUTYH variants, but the pathogenic partner and phase relative to p.G25D were not established.

PM5 Not met: no alternate missense variant at MUTYH Gly25 has an established pathogenic classification, and zero same-residue candidates were identified.

PM6 Not assessed: no parental testing or presumed de novo evidence is documented for p.Gly25Asp.

PP1 Not assessed: no affected-relative genotypes, unaffected-relative testing, or informative meioses are reported for p.Gly25Asp.

PP2 Not met: MUTYH has an established loss-of-function mechanism and documented missense variation, without evidence that pathogenic variants are predominantly missense.

PP3 Not met: REVEL 0.111 is below the >=0.644 PP3 supporting threshold for this missense variant.

PP4 Not met: reported adenomatous polyposis and colorectal cancer are not sufficiently specific because the linked p.P18L-p.G25D combination also occurred in three controls.

PP5 Not met: ClinVar lists zero expert-panel submissions for this exact variant, and the available assertions are non-expert laboratory classifications.

Benign

BA1 Not met: the highest observed frequency is 1.30313%, below the generic BA1 stand-alone threshold of 5%.

BS2 Not assessed: gnomAD shows 4–7 homozygotes, but their health status, age, and MUTYH disease phenotypes are not established.

BS4 Not assessed: no adequately tested affected family members or documented non-segregation are available for p.Gly25Asp.

BP1 Not met: MUTYH has a loss-of-function mechanism, but substantial missense variation and missense functional testing prevent calling missense variants generally benign.

BP2 Not assessed: p.G25D was in cis with p.P18L, but p.P18L was not established as pathogenic or likely pathogenic for the recessive disorder.

BP5 Not assessed: additional MUTYH variants were reported, but none was established as a convincing alternative pathogenic explanation for the patient's phenotype.

BP6 Not met: ClinVar lists zero expert-panel submissions for this exact variant, despite several ordinary laboratory Benign or Likely benign assertions.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000441106; MAF= 0.04411%, 712/1614126 alleles, homozygotes = 7) and has highest observed frequency in the East Asian population (AF= 0.0113403; MAF= 1.13403%, 509/44884 alleles, homozygotes = 7); grpmax FAF= 0.0105262.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00105347; MAF= 0.10535%, 298/282876 alleles, homozygotes = 4) and has highest observed frequency in the East Asian population (AF= 0.0130313; MAF= 1.30313%, 260/19952 alleles, homozygotes = 4); grpmax FAF= 0.0133151.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.044% · 712 / 1,614,126
7 hom · FAF 1.1%

East Asian 509 / 44,884	1.1% 7 hom
South Asian 127 / 91,082	0.14%
Remaining individuals 37 / 62,506	0.059%
Middle Eastern 1 / 6,062	0.016%
Admixed American 2 / 60,010	0.0033%
European (non-Finnish) 36 / 1,180,006	0.0031%

+ 4 not observed (European (Finnish), Amish, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.11% · 298 / 282,876
4 hom · FAF 1.3%

East Asian 260 / 19,952	1.3% 4 hom
South Asian 32 / 30,616	0.1%
Remaining individuals 3 / 7,226	0.042%
European (non-Finnish) 3 / 129,182	0.0023%

+ 4 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Likely benign (2 clinical laboratories) and as likely benign (1 clinical laboratory). (ClinVarID = 41763)

ClinVar ↗

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.111. BayesDel score = -0.17848.

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107443475, n = 4 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Germline mutations of the MYH gene in Korean patients with multiple colorectal adenomas.

PMID 17703316 ↗ · Kim DW et al. · 2007 Oct CLINVAR · case observation

Searched

c.74G>ANP_001121897.1:p.(G25D)p.G25DG25D

Found

The paper reports MUTYH p.G25D in cis with p.P18L in one FAP patient and in three of 96 normal controls. Cloning and sequencing established that the two substitutions were on the same allele; the report did not establish G25D as pathogenic.

Variant

✓ Names this variant — characterised directly

Applied to

→BS1 strong

Provides independent control-cohort frequency context for the p.G25D-containing haplotype.

Monoallelic MYH variants were identified in 3 (4.8%) of 62 study patients. Two patients with multiple polyps displayed a monoallelic p.A359Vand p.IVS10-2A>G mutation, respectively, whereas an FAP patient contained p.P18L-p.G25D. In the 96 normal controls, monoallelic MYH variants were identified in eight individuals, specifically, p.A359V in four, p.P18L-p.G25D in three, and p.Q253X in one patient.

Location Results, paragraph 4; Table 2, patient 5; Discussion, Frequency of germline MYH mutations and genotypic characteristics · Context Bidirectional sequencing of all 16 coding exons in 62 Korean patients and 96 normal controls; variants were confirmed by re-amplification, cloning, and sequencing, including allele phasing. · full text

A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese.

PMID 18811933 ↗ CLINVAR · functional

Searched

c.74G>ANP_001121897.1:p.(G25D)p.Gly25Asp

Found

The paper reports c.74G>A encoding p.Gly25Asp as part of a c.53C>T-c.74G>A haplotype. The isolated p.Gly25Asp protein remained mitochondrial like wild type in COS-7-cell immunofluorescence, whereas the combined p.Pro18Leu/p.Gly25Asp haplotype showed dual nuclear and mitochondrial localization.

Variant

✓ Names this variant — characterised directly

Applied to

→BS1 strong

Provides independent healthy-control frequency context for the c.74G>A-containing haplotype.

→BS3 supporting

Isolated p.Gly25Asp showed wild-type-like mitochondrial localization, providing secondary evidence against a localization defect.

Interestingly, immunofluorescence showed that the hMYH proteins with single missense mutation, p.Pro18Leu or p.Gly25Asp, remained in the mitochondria, similar to the wild-type protein.

Location Results, Distinct subcellular localization of wild- and variant-type hMYH protein; Results, Association analysis of the c.53C>T/c.74G>A variation with sporadic CRC · Context Association analysis in 138 Chinese sporadic colorectal cancer patients and 343 healthy controls; COS-7-cell expression of wild-type, single-mutant, and combined-mutant hMYH-FLAG proteins with immunofluorescence microscopy. · full text

Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.

PMID 25820570 ↗ · Komine K et al. · 2015 Jul CLINVAR · functional

Searched

c.74G>Ap.(G25D)p.G25D

Found

The paper evaluates MUTYH p.G25D in a MutY-deficient E. coli complementation assay and classifies it as functionally retained under the study's assay-specific thresholds. The paper also states that more than 200 MUTYH missense variants have been detected.

Variant

✓ Names this variant — characterised directly

Applied to

→BS3 supporting

Direct controlled complementation assay classified p.G25D as functionally retained below the study's 1.7-fold defect threshold.

According to this categorization, 17 variants (p.V22M, p.G25D, p.D105N, p.I223V, p.V246F, p.G286E, p.Q338H, p.Q338R, p.Q414R, p.L420M, p.R426C, p.R437Q, p.A473T, p.S515F, p.P516L, p.L529M, and p.R534Q) were functionally retained, 17 variants (p.P18L, p.Y128H, p.P157L, p.G189E, p.A227V, p.V234M, p.R241W, p.R245C, p.R309C, p.P380T, p.G396D, p.P405S, p.R437P, p.A489T, p.V493F, p.G503E, and p.E480del) were partially defective, and 13 variants (p.W103R, p.W131R, p.Y179C, p.R182C, p.R182H, p.R185Q, p.R245H, p.R274W, p.C290W, p.P295L, p.L388P, p.P405L, and p.A473D) were functionally defective (Fig. 1B; Table1).

Location Results, BER Detection with a MutY-Deficient E. coli Complementation Assay; Table 1 · Context MutY-deficient E. coli CC104mutY complementation assay measuring rifampicin-resistant mutation rates; 47 MUTYH variants were tested using MUTYH type 2/isoform 4. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

17060676 ↗ ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. CLINVAR

18422726 ↗ Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis. CLINVAR

22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. CLINVAR

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. 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

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