MUTYH c.920G>A, p.Arg307Gln
NM_001128425.2:c.920G>A
COSMIC ID: COSM9494877
Variant of Uncertain Significance (VUS)
The R307Q variant in MUTYH is present at extremely low frequency in population databases (PM2) and computational evidence supports benign impact (BP4), but no functional, segregation, or case-control evidence is available. The combination of one moderate pathogenic and one supporting benign criterion yields a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
BP4
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.920G>A
Protein Change
R307Q
Location
Exon 10
(Exon 10 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 307 in gene MUTYH
Alternate Identifiers
COSM9494877
Variant interpretation based on transcript NM_001128425.2
Genome Browser
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HGVS InputNM_001128425:c.920G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00778%
Rare
Highest in Population
African/African American
0.0241%
Low Frequency
Global: 0.00778%
African/African American: 0.0241%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282662Alt: 22Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00778%, 22/282662 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0241%, 6/24920 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
6 VUS
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Variant summary: MUTYH c.920G>A (p.Arg307Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251290 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (7.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.920G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast cancer/unspecified advanced cancer (e.g. Mandelker_2017, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. A co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA1 c.2457delC, p.Asp821fsX25; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28944238, 28873162, 25186627). ClinVar contains an entry for this variant (Variation ID: 141135). Based on the evidence outlined above, the variant was classified as uncertain significance.
The MUTYH c.920G>A (p.Arg307Gln) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 29212164 (2017), 30267214 (2018), 28944238 (2017)), breast cancer (PMID: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) or an unspecified cancer (PMID: 28873162 (2017)). This variant has also been reported in reportedly unaffected individuals (PMID: 29641532 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 307 of the MUTYH protein (p.Arg307Gln). This variant is present in population databases (rs140156029, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or an unspecified cancer (PMID: 25186627, 28873162). ClinVar contains an entry for this variant (Variation ID: 141135). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 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 307 in gene MUTYH
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.99
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 multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: R307Q is a missense change, not a null variant. Therefore, this criterion is not applied.
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 previously established pathogenic variant with the same R307Q amino acid change. Therefore, this criterion is not applied.
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. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established 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.
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 or cohort data demonstrating enrichment. Therefore, this criterion is not applied.
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 without benign variation." The evidence for this variant shows: R307 is not in a recognized mutational hotspot or critical domain defined by VCEP. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: present in gnomAD at MAF 0.00778% overall and 0.0241% in African/African American, consistent with extremely low frequency for a recessive gene. Therefore, this criterion is applied at Moderate strength.
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 data on phase with other pathogenic variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants." The evidence for this variant shows: R307Q is a missense change without length alteration. Therefore, this criterion is not applied.
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 is pathogenic." The evidence for this variant shows: no other missense variants at residue R307 classified as pathogenic. Therefore, this criterion is not applied.
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.
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. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with 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 missense and LOF disease mechanisms and some benign variation; gene‐specific VCEP guidance does not recommend PP2. Therefore, this criterion is not applied.
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: CADD score 2.99 (benign range), SpliceAI 0.21 (low splicing impact), other tools not supportive of damage. Therefore, this criterion is not applied.
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 phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar submissions are VUS or Likely benign; no reputable source assertion of pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The evidence for this variant shows: MAF 0.00778%, well below 5%. Therefore, this criterion is not applied.
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: frequency is extremely low for a recessive gene and below disease‐expected thresholds. Therefore, this criterion is not applied.
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 disorder or full‐penetrance condition." The evidence for this variant shows: no healthy adult genotype data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well‐established functional studies show no damaging effect." The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
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.
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: MUTYH disease mechanism includes both missense and truncating variants; no gene‐specific guidance for BP1. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
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: R307Q is not an in‐frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence support a benign effect on the gene or gene product." The evidence for this variant shows: CADD score 2.99, SpliceAI 0.21, and other in silico tools do not predict a damaging effect. Therefore, this criterion is applied at Supporting strength.
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 alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: ClinVar submissions are VUS or Likely benign but without detailed evidence; BP6 is discouraged. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and low conservation." The evidence for this variant shows: R307Q is a missense change. Therefore, this criterion is not applied.