MSH6 c.2830A>G, p.Ile944Val
NM_000179.3:c.2830A>G
COSMIC ID: COSM1021282
Variant of Uncertain Significance (VUS)
NM_000179.3:c.2830A>G (I944V) in MSH6 is classified as VUS. It meets only PM2_Supporting (extremely rare in controls) and BP4_Supporting (no predicted splicing impact) with insufficient additional evidence to classify as benign or pathogenic.
ACMG/AMP Criteria Applied
PM2
BP4
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.2830A>G
Protein Change
I944V
Location
Exon 4
(Exon 4 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 944 in gene MSH6
Alternate Identifiers
COSM1021282
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.2830A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0012%
Rare
Highest in Population
Admixed American
0.0029%
Rare
Global: 0.0012%
Admixed American: 0.0029%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250456Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0012%, 3/250456 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.0029%, 1/34530 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
7 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (1 clinical laboratories) and as Uncertain Significance (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 944 in gene MSH6
Functional Summary
The MSH6 I944V variant has not been functionally characterized, and its effect on MSH6 protein function is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.505
0.505
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 3.41polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1/2 splice sites) causing LOF in MSH6. The variant NM_000179.3:c.2830A>G is a missense (I944V) change. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires the same amino acid change as a previously established pathogenic variant. There is no reported pathogenic variant encoding I944V in MSH6. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo variants with parental testing. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-validated functional assays showing a deleterious effect on MSH6 function. No functional studies are available for I944V. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires statistically significant enrichment in affected individuals versus controls. No case-control or patient cohort data exist for I944V. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants located in mutational hot spots or well-established functional domains without benign variation. I944V lies outside characterized critical domains of MSH6. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 supporting strength applies to variants absent or extremely rare (<1 in 50,000 alleles) in gnomAD v4. The variant has MAF=0.0012% (1.2e-5), below 1/50,000. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive disorders with detected trans observations. MSH6 is autosomal dominant and no in trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes such as in-frame indels. I944V is a missense variant. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies when a different missense change at the same residue is classified as pathogenic. No other pathogenic missense at codon 944 is reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to presumed de novo variants without parental confirmation. No de novo data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires segregation data in families. No segregation information is available for I944V. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation rate. MSH6 has known pathogenic missense variants and benign variation; no gene-specific evidence supports PP2 here. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 supporting requires HCI prior >0.68 or predicted splice defect; this variant has mixed computational predictions and no splicing impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires tumor phenotype or MSI/IHC consistent with MSH6 deficiency. No tumor or IHC data are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to reputable database assertions of pathogenicity. ClinVar reports only VUS or likely benign for this variant. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 standalone applies to MAF ≥0.22%. The variant MAF=0.0012% is below this threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 strong applies to MAF between 0.022%–0.22%. The variant MAF=0.0012% is below 0.022%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when observed in trans with a pathogenic variant in an LS patient without early CMMRD signs. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional assays demonstrating no impact. No such assays are available for I944V. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of segregation in families. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. MSH6 pathogenicity includes missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observation in trans with a pathogenic variant for a dominant gene. No trans observations exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. I944V is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 supporting applies when SpliceAI predicts no splicing impact (delta ≤0.1) or HCI prior <0.11. SpliceAI shows no splicing impact for I944V. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when another cause for disease is identified in the same individual. No such cases are reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to assertions of benign impact by reputable sources without evidence. No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous/intronic variants. I944V is missense. Therefore, BP7 is not applied.