MUTYH c.200G>T, p.Gly67Val
NM_001128425.2:c.200G>T
COSMIC ID: COSM8720079
Variant of Uncertain Significance (VUS)
NM_001128425.2:c.200G>T (G67V) in MUTYH is classified as Variant of Uncertain Significance. It is absent from population databases (PM2) and reported as benign by a reputable source (BP6), but lacks additional functional, segregation, or case–control evidence to support a definitive pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
BP6
Genetic Information
Gene & Transcript Details
Gene
MUTYH
Transcript
NM_001128425.2
Total Exons
16
Strand
Reverse (−)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001128425.1 | RefSeq Select | 16 exons | Reverse |
Variant Details
HGVS Notation
NM_001128425.2:c.200G>T
Protein Change
G67V
Location
Exon 3
(Exon 3 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 67 in gene MUTYH
Alternate Identifiers
COSM8720079
Variant interpretation based on transcript NM_001128425.2
Genome Browser
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HGVS InputNM_001128425:c.200G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 67 in gene MUTYH
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.34
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (G67V), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet the rule.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no other pathogenic variant at codon 67 has been reported. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows: no case–control data reporting increased prevalence in cases. Therefore, this criterion is not applied at Not Applied strength because there is no statistical evidence of enrichment in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." The evidence for this variant shows: no specific hot spot or critical domain designation for codon 67 in MUTYH. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a documented mutational hot spot or critical domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes, or ExAC." The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large population cohorts.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no information on allelic phase with another pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because trans configuration data is unavailable.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a single amino acid substitution without change in protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: no other pathogenic missense changes have been reported at codon 67. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic missense at the same residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied at Not Applied strength because assumed de novo status cannot be evaluated.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied at Not Applied strength because family segregation has not been assessed.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease." The evidence for this variant shows: MUTYH has both benign and pathogenic missense variants; gene-specific missense constraint is not clearly met. Therefore, this criterion is not applied at Not Applied strength because the gene does not meet PP2 specificity requirements.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico tools (CADD, SpliceAI) do not predict a damaging effect. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support pathogenicity.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no clinical phenotype or family history data provided. Therefore, this criterion is not applied at Not Applied strength because phenotypic specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied at Not Applied strength because there is no pathogenic assertion.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes, or ExAC." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because the frequency is below the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: allele frequency is 0%, not greater than expected. Therefore, this criterion is not applied at Not Applied strength because frequency is too low.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (full penetrance expected) X-linked or mitochondrial disorder." The evidence for this variant shows: no data on healthy adult observations. Therefore, this criterion is not applied at Not Applied strength because healthy individual data are unavailable.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation information is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: missense is an established mechanism in MUTYH. Therefore, this criterion is not applied at Not Applied strength because missense variants are a known mechanism of disease in this gene.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no data on cis/trans phase with other variants. Therefore, this criterion is not applied at Not Applied strength because allelic context is unknown.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: the change is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because BP3 does not apply to missense variants.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: computational predictions (CADD, SpliceAI) are benign but were deemed insufficiently strong. Therefore, this criterion is not applied at Not Applied strength because in silico evidence alone is inconclusive.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no other molecular diagnoses reported. Therefore, this criterion is not applied at Not Applied strength because no alternate cause has been documented.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but with no evidence available to perform an independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Benign by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable source has classified it as benign without primary evidence.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and not conserved." The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.