MSH6 c.3104G>A, p.Arg1035Gln
NM_000179.3:c.3104G>A
COSM6956244, COSM6960044
Population Frequency
0.00282%
Low Frequency
ClinVar Classification
Uncertain Significance (VUS)
7 publications
REVEL Score
0.825
Likely Pathogenic
COSMIC Recurrence
2 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
MSH6
Transcript
NM_000179.3
MANE Select
Total Exons
10
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 10 exons | Forward |
| NM_000179.1 | Alternative | 10 exons | Forward |
Variant Details
HGVS Notation
NM_000179.3:c.3104G>A
Protein Change
R1035Q
Location
Exon 4
(Exon 4 of 10)
5'
Exon Structure (10 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1035: R1035L
Alternate Identifiers
COSM6956244, COSM6960044
Variant interpretation based on transcript NM_000179.3
Clinical Evidence
Global Frequency
0.00282%
Rare
Highest in Population
African/African American
0.00617%
Rare
Global: 0.00282%
African/African American: 0.00617%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 248120
Alt: 7
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00282%, 7/248120 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00617%, 1/16208 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
7 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratories).
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
ClinVar reports other pathogenic variants at position 1035: R1035L
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The MSH6 R1035Q variant has not been functionally characterized.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.825
0.825
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
metasvm: D
metalr: D
Benign:
CADD: 4.66
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the PVS1 rule applies to null variants (nonsense, frameshift, canonical splice site variants) where loss‐of‐function is a known mechanism of disease. The rule states: 'Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6' (or similar for splicing). The evidence for this variant shows it is a missense change (R1035Q) and does not result in a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, PS1 applies when the same amino acid change has been previously established as pathogenic via a different nucleotide change. The rule states: 'Predicted missense substitution with the same amino acid change as a previously established pathogenic variant.' The evidence for this variant shows no such alternate nucleotide change or prior classification. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines (and VCEP modifications), PS2 requires de novo occurrence with parental confirmation. The rule states: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant does not include any de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing notes and standard ACMG guidelines, PS3 requires calibrated functional assay evidence showing deleterious effect. The finding states: 'The MSH6 R1035Q variant has not been functionally characterized.' The evidence for this variant shows no functional study support. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS4 pertains to statistically increased prevalence in affected individuals compared to controls. The rule states: 'Prevalence in affected individuals is significantly increased versus controls.' The evidence for this variant does not include case-control or prevalence data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 applies for variants in mutational hotspots or critical functional domains that do not have benign variation. The rule states: 'Missense changes in a mutational hotspot or critical functional domain.' The evidence for this variant does not provide information that the affected residue is within such a hotspot beyond the PM5 evidence. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2, the rule is: 'Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence for this variant shows a minor allele frequency (MAF) of 0.00282% (7/248120 alleles), which is extremely rare and below the defined cutoff. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 is used for recessive disorders where detection of the variant in trans with a pathogenic variant is documented. The rule states: 'Detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant does not include such observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 is for in-frame deletions/insertions or protein length changes. The rule states: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region.' The evidence for this variant indicates a missense change and no protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 applies when a novel missense change occurs at an amino acid residue where a different missense change has been classified as pathogenic, provided that PP3 is also supporting. The rule states: 'Missense change at an amino acid residue where a different missense change was classified as pathogenic on the protein level.' The evidence for this variant indicates that at residue R1035, another missense change has been determined to be pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 refers to assumed de novo status without confirmation. The rule states: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant does not include such data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP1 relates to cosegregation with disease in multiple affected family members. The rule states: 'Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio h >2.08 (Supporting) to >18.7 (Strong).' The evidence for this variant does not include segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 applies to genes with a low rate of benign missense variation in which missense variants are a common mechanism of disease. The rule states: 'Missense variant in a gene with low benign variation.' The evidence for this variant does not provide specific data supporting the application of PP2. Therefore, this criterion is not applied.
PP3
PP3 (Moderate)
Strength Modified
According to VCEP guidelines for PP3, the rule is: 'Moderate Missense variant with HCI prior probability for pathogenicity >0.81 as per https://hci-priors.hci.utah.edu/PRIORS.' The evidence for this variant includes a REVEL score of 0.82, which meets the threshold (>0.81) and multiple computational tools support a deleterious effect. Therefore, this criterion is applied at Moderate strength.
PP4
PP4 (Not Applied)
Strength Modified
According to disease-specific ACMG guidelines, PP4 applies when there is significant phenotype specificity or supporting tumor data. The rule states: 'Supporting evidence from a highly specific phenotype or tumor profile consistent with the gene.' The evidence for this variant does not include tumor or phenotype segregation data specific to MSH6. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 applies when reputable sources such as ClinVar report the variant as pathogenic. The rule states: 'Reputable source reports variant as pathogenic.' The evidence from ClinVar for this variant shows conflicting interpretations (VUS and Likely Benign). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines for BA1, the rule is: 'Stand Alone evidence when the allele frequency is ≥0.22% in gnomAD v4 for MSH6, excluding founder variants.' The evidence for this variant shows a MAF of 0.00282%, which is far below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines for BS1, the rule is: 'Allele frequency is greater than expected for the disorder, typically between 0.022% and 0.22%.' The evidence for this variant shows a frequency (0.00282%) much lower than that range. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to disease-specific guidelines, BS2 applies when the variant is observed in a healthy individual beyond the expected age of onset. The rule states: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age.' The evidence for this variant does not include such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS3 applies when well-established functional studies show no damaging effect. The rule states: 'Calibrated functional assays that demonstrate no deleterious effect (functional odds for pathogenicity ≤0.05).' The evidence for this variant indicates that functional studies have not been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 applies when there is a lack of segregation of the variant with disease in families. The rule states: 'Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio h <0.05.' The evidence for this variant has no segregation information. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where truncating variants are known to cause disease. The rule states: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' The evidence for MSH6 shows that missense variants can be pathogenic and there is no indication this variant has a benign mechanism. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 applies when the variant is observed in trans with a pathogenic variant or in cis with a benign variant in a manner inconsistent with a pathogenic role. The rule states: 'In trans with a pathogenic variant in dominant disorders or cis with a benign variant.' The evidence for this variant does not include such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 concerns in-frame deletions/insertions in repetitive regions with no predicted impact. The rule states: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant is a missense substitution rather than an in-frame indel; therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines for BP4, the rule is: 'Supporting evidence from multiple computational tools that predict no impact on protein function (e.g., HCI prior probability <0.11).' The evidence for this variant shows a high REVEL score (0.82) and other computational tools supporting deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to disease-specific ACMG guidelines, BP5 applies when the phenotype is inconsistent with the gene’s role or there is evidence from tumor markers inconsistent with the variant. The rule states: 'Multiple tumors with features inconsistent with the gene’s established function.' The evidence for this variant does not include such tumor or phenotype data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source asserts the variant is benign. The rule states: 'Multiple reputable sources classify the variant as benign (with no functional data to the contrary).' The evidence for this variant in ClinVar is conflicting, with some labs reporting VUS or Likely Benign, and does not fulfill a uniform benign classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous changes or intronic variants predicted to have no splicing impact. The rule states: 'A synonymous variant or an intronic variant at or beyond ±7 not predicted to affect splicing.' The evidence for this variant indicates a missense change, not a synonymous or deep intronic change. Therefore, this criterion is not applied.