About MUTYH
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MUTYH c.1255G>A, p.(Ala419Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen MUTYH VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
141 / 1,614,058 alleles
gnomAD v4.1: 141 / 1,614,058 alleles. Recorded AF 8.73575e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.72424e-05; MAF= 0.00672%, 19/282560 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000131779; MAF= 0.01318%, 17/129004 alleles, homozygotes = 0); grpmax FAF= 8.819e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
13 reported laboratory submissions
10 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MUTYH VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00672%
- 19/282
- 560 alleles
- 0 homozygotes.
- gnomAD v4.1: AF=0.00874%
- 141/1
- 614
- 058 alleles
- 1 homozygote.
- Absent from gnomAD-Canada v1.0.
- grpmax FAF=8.819e-05 (v2.1)
- 8.341e-05 (v4.1).
Still missing
- Phenotype of the single gnomAD v4.1 homozygote is unknown.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (below 0.5 threshold).
- BayesDel: -0.184886 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
- ClinVar submitters concur: multiple in silico tools predict benign.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No evidence that the same amino acid change (p.Ala419Thr) has been established as pathogenic in a different nucleotide change in MUTYH. Details ▾Hide ▴
Evidence considered
- No prior pathogenic assertion for p.Ala419Thr via alternate nucleotide change found in ClinVar or literature.
Still missing
- No alternate nucleotide changes producing p.Ala419Thr identified.
PS2 No de novo observation reported for this variant. No parentage-confirmed de novo data available in ClinVar submissions or published literature. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified.
Still missing
- No de novo testing data available for this variant.
PS3 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. Details ▾Hide ▴
Evidence considered
- Multiple ClinVar submissions confirm absence of published functional studies. REVEL score of 0.414 is borderline
- BayesDel -0.185 is benign-leaning.
- OncoKB classification: Unknown Oncogenic Effect with no variant-specific functional evidence.
Still missing
- No published functional assay data for NM_001128425.2:c.1255G>A.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 19/282
- 560 alleles (0.0067%). gnomAD v4.1: 141/1
- 614
- 058 alleles (0.0087%)
- 1 homozygote. Absent from gnomAD-Canada.
- ClinVar reports in individuals with colorectal cancer and suspected Lynch syndrome
- but no controlled enrichment analysis.
Still missing
- No case-control odds ratio or statistically significant enrichment data.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- exact variant not listed in hotspot database.
PM6 No de novo observation reported for this variant. No parentage-confirmed data available. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified in ClinVar
- literature
- or databases.
Still missing
- No de novo testing data.
PP1 No segregation data available. No family studies demonstrating cosegregation of this variant with disease phenotype have been identified. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar or published literature.
Still missing
- No family segregation analysis available.
PP2 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. Details ▾Hide ▴
Evidence considered
- MUTYH disease mechanism involves both missense and truncating variants
- PP2 requires gene-level benign missense constraint evidence not available from existing data.
Still missing
- No gene-specific benign missense constraint metric (e.g.
- missense Z-score
- gnomAD constraint) evaluated.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.414 (below 0.5 pathogenic threshold).
- BayesDel score: -0.184886 (benign-leaning).
- SpliceAI max delta: 0.00 (no splice impact).
- ClinVar submitters report multiple in silico tools predict benign effect.
Sources
PP4 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. Details ▾Hide ▴
Evidence considered
- MUTYH-associated polyposis phenotype overlaps with other hereditary CRC syndromes.
- Variant reported in individuals with heterogeneous phenotypes (CRC
- Lynch syndrome
- breast cancer).
Still missing
- No detailed phenotype data for individual carriers.
Sources
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: 10 labs = Uncertain significance
- 1 = Uncertain Significance
- 1 = Benign (Ambry)
- 1 = Likely benign (Invitae).
- No reputable source classifies as pathogenic.
Sources
BA1 The variant frequency in gnomAD is well below the 1% BA1 threshold (v2.1: AF=0.0067%; v4.1: AF=0.0087%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0067%
- v4.1 AF=0.0087%
- both well below 1% BA1 threshold.
Sources
BS1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0067%
- v4.1 AF=0.0087%
- both below 0.3% BS1 threshold.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- 1 homozygote in gnomAD v4.1
- but phenotype unknown. No confirmed observation in a healthy homozygous adult.
Still missing
- Phenotype data for the single gnomAD v4.1 homozygote not available.
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- No published functional studies for this variant. In silico scores are computational predictions
- not functional evidence.
- ClinVar submitters confirm absence of functional studies.
Still missing
- No in vitro functional assay data for NM_001128425.2:c.1255G>A.
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease. No family studies involving this variant have been identified. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation analysis.
BP1 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. Details ▾Hide ▴
Evidence considered
- MUTYH has established pathogenic missense variants (Y165C
- G382D
- etc.) with functional evidence of impaired glycosylase activity.
- BP1 is specific to genes where the primary disease mechanism is exclusively truncating.
Sources
BP2 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. Details ▾Hide ▴
Evidence considered
- No evidence of co-occurrence in trans with a pathogenic MUTYH variant in a healthy individual.
Still missing
- No phasing data available.
BP5 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. Details ▾Hide ▴
Evidence considered
- No evidence of alternate molecular diagnosis in carriers of this variant.
Still missing
- No data on co-occurring molecular diagnoses.
BP6 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. Details ▾Hide ▴
Evidence considered
- Ambry Genetics: Benign (SCV000185354). Labcorp/Invitae: Likely benign (SCV000166445).
- Internal evidence supporting these benign classifications not available for independent verification.
- Majority classification is VUS (11/14 submissions).
Still missing
- Ambry and Invitae benign classification criteria and internal data not publicly accessible.
Sources
PS5 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). Details ▾Hide ▴
Evidence considered
- No functional assay data
- in silico scores are not strongly pathogenic.
Still missing
- No functional evidence to support PS5.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant.
Sources
pvs1_variant_assessment
PM3 N/ASkipped per adjudication instructions — trivially not applicable (requires recessive disorder with second pathogenic allele in trans; not on assess list). Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per adjudication instructions — trivially not applicable (protein length change criterion; variant is a substitution). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo 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). Details ▾Hide ▴
Evidence considered
- No same-residue comparator with established pathogenicity identified.
Sources
pm5_candidates
BP3 N/ASkipped per adjudication instructions — trivially not applicable (in-frame indel criterion, variant is a substitution). Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is specific to synonymous variants.
Identifiers
- Gene
- MUTYH
- Transcript
- NM_001128425.2
- Coding (HGVS c.)
- NM_001128425.2:c.1255G>A
- Protein (HGVS p.)
- NP_001121897.1:p.(Ala419Thr)
- GRCh38
- chr1:45331488 C>T
- GRCh37
- chr1:45797160 C>T
- ClinVar
- 4113201, 135983
Gene diagram
Every interpreted variant in MUTYH, mapped onto the exon structure of NM_001128425.2. Select a row to find it on the plot.
MUTYHNM_001128425.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MUTYH
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
141 / 1,614,058 alleles
AF 8.74e-05 · 1 homozygotes · FAF 8.34e-05
gnomAD v2.1
19 / 282,560 alleles
AF 6.72e-05 · 0 homozygotes · FAF 8.82e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 8.7e-05 · 141 / 1,614,058 alleles · 1 hom · FAF 8.3e-05
| Remaining individuals23 / 62,488 | 0.00037 |
| European (non-Finnish)116 / 1,180,042 | 9.8e-051 hom |
| African/African American2 / 74,944 | 2.7e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 6.7e-05 · 19 / 282,560 alleles · 0 hom · FAF 8.8e-05
| European (non-Finnish)17 / 129,004 | 0.00013 |
| African/African American2 / 24,934 | 8e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.73575e-05; MAF= 0.00874%, 141/1614058 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.000368071; MAF= 0.03681%, 23/62488 alleles, homozygotes = 0); grpmax FAF= 8.341e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.72424e-05; MAF= 0.00672%, 19/282560 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000131779; MAF= 0.01318%, 17/129004 alleles, homozygotes = 0); grpmax FAF= 8.819e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.414
- BayesDel
- -0.185
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (below 0.5 threshold).
- BayesDel: -0.184886 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
- ClinVar submitters concur: multiple in silico tools predict benign.
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.414 (below 0.5 pathogenic threshold).
- BayesDel score: -0.184886 (benign-leaning).
- SpliceAI max delta: 0.00 (no splice impact).
- ClinVar submitters report multiple in silico tools predict benign effect.
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is specific to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = -0.184886.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 23852704 ↗Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.European Group on Tumor Markers 2014 guidelines for biomarkers in colorectal, gastric, and GIST cancers. Discusses CEA, KRAS, and other tumor markers. Does not mention MUTYH or any MUTYH variants; genetic susceptibility markers were explicitly excluded from scope.Does not name this variant
Quoted passage
Genetic susceptibility markers are not discussed in this article.
Full text reviewed; MUTYH and the variant not found. Paper explicitly states genetic susceptibility markers are not discussed.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.ACG clinical guideline on genetic testing and management of hereditary gastrointestinal cancer syndromes, including MAP, Lynch syndrome, FAP, and others. Provides surveillance and management recommendations for known syndromes but does not discuss individual MUTYH variants.Does not name this variant
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PMID 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.ACMG/AMP standards and guidelines for interpretation of sequence variants (Richards et al. 2015). This is the foundational generic classification framework paper; it does not discuss any specific MUTYH variants.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Description of a standardized DNA variant scoring system for pathogenicity assessment in Mendelian disorders (Karbassi et al. 2016). Does not discuss specific MUTYH variants.Does not name this variant
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PMID 26689913 ↗Patterns and functional implications of rare germline variants across 12 cancer types.Lu C et al. · 2015Analysis of rare germline variants across 12 cancer types from TCGA (Lu et al. 2015). Identifies cancer-susceptibility gene variants in tumor-normal paired sequencing data. MUTYH is among the genes analyzed as a cancer susceptibility gene, but NM_001128425.2:c.1255G>A (p.Ala419Thr) was not specifically identified or discussed in the abstract.Does not name this variant
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PMID 17161978 ↗MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing.Cheadle JP et al. · 2007Review of MUTYH-associated polyposis covering mutation spectrum, functional studies of five missense variants (Y165C, R227W, V232F, G382D, A459D), and clinical testing. NM_001128425.2:c.1255G>A (p.Ala419Thr) is not mentioned in this paper.Does not name this variant
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PMID 17581577 ↗Base-excision repair of oxidative DNA damage.David SS et al. · 2007Nature review of base-excision repair of oxidative DNA damage, focusing on structural biology of OGG1 and MutM/MUTYH glycosylases. NM_001128425.2:c.1255G>A (p.Ala419Thr) is not mentioned.Does not name this variant
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PMID 19725997 ↗Base excision repair and the role of MUTYH.Kairupan C et al. · 2007Review of base excision repair and the role of MUTYH in colorectal cancer. NM_001128425.2:c.1255G>A (p.Ala419Thr) is not mentioned.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria (Nykamp et al. 2017). A refinement framework for variant classification; does not discuss specific MUTYH variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
141 / 1,614,058 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
10 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1742141534
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/135983/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-45797160-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-45331488-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-45331488-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001128425.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/MUTYH/A419T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MUTYH+c.1255G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.73575e-05; MAF= 0.00874%, 141/1614058 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.000368071; MAF= 0.03681%, 23/62488 alleles, homozygotes = 0); grpmax FAF= 8.341e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.72424e-05; MAF= 0.00672%, 19/282560 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000131779; MAF= 0.01318%, 17/129004 alleles, homozygotes = 0); grpmax FAF= 8.819e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 135983)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = -0.184886.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.