MSH6 c.2889C>T, p.Gly963=
NM_000179.3:c.2889C>T
Variant of Uncertain Significance (VUS)
This synonymous MSH6 variant has no predicted splicing impact, is extremely rare in population databases, and meets two benign supporting (BP4, BP7) and one pathogenic supporting (PM2) criteria. Conflicting supporting evidence leads to classification as VUS.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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.2889C>T
Protein Change
G963=
Location
Exon 4
(Exon 4 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.2889C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.002%
Rare
Highest in Population
East Asian
0.0273%
Low Frequency
Global: 0.002%
East Asian: 0.0273%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249516Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.002%, 5/249516 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0273%, 5/18348 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
3 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratories) and 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.66
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6... or canonical ±1/2 splice variants causing frameshift leading to NMD." The evidence for this variant shows: it is a synonymous (G963=) change with no predicted loss‐of‐function. Therefore, this criterion is not applied because the variant does not result in a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong – A predicted missense substitution encoding the same amino acid change as a previously established Pathogenic variant." The evidence for this variant shows: it is synonymous with no amino acid change. Therefore, this criterion is not applied because it does not alter the amino acid.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong – ≥4 de novo points based on confirmed de novo occurrence." The evidence for this variant shows: no de novo evidence is available. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong – Calibrated functional assays with OddsPath >18.7 indicate deleterious effect." The evidence for this variant shows: no functional assay data are available. Therefore, this criterion is not applied due to absence of functional studies.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Strong – Statistically significant case-control enrichment of variant in affected individuals." The evidence for this variant shows: no case-control or epidemiological data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Moderate – Located in a mutational hotspot or critical functional domain without benign variation." The evidence for this variant shows: it is a synonymous change outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting – Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4." The evidence for this variant shows: MAF = 0.002% (5/249,516 alleles, ~1/49,903), meeting the rarity threshold. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Applicable for recessive disorders when observed in trans with a pathogenic variant." The evidence for this variant shows: no trans observations in recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate – Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate – Missense change at an amino acid residue where a different missense change is Pathogenic." The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Supporting – Assumed de novo occurrence without confirmed parentage." The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting – Co-segregation with disease with combined LOD >2.08." 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: "Supporting – Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting – Predicted splice defect for non-canonical splice nucleotides with SpliceAI delta ≥0.2 or HCI prior >0.68." The evidence for this variant shows: SpliceAI delta = 0, CADD = 0.66, indicating no deleterious prediction. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting – Tumor phenotype (MSI-H or loss of MMR) in multiple independent tumors consistent with gene." The evidence for this variant shows: no tumor or MSI/MMR data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting – Reputable source reports variant as pathogenic without primary evidence." The evidence for this variant shows: ClinVar submissions include VUS and Likely Benign, not Pathogenic. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong – gnomAD v4 allele frequency ≥0.00022 and <0.0022." The evidence for this variant shows: MAF = 0.00002, below the BS1 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong – Observed in trans with a pathogenic variant in a healthy adult for dominant disorders." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong – Well‐validated functional assays show no impact on protein or mRNA." The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Strong – Lack of segregation in multiple affected family members." 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: "Supporting – Missense variant in gene where only truncating variants cause disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting – Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting – In-frame indels in repetitive region without known function." The evidence for this variant shows: it is a single nucleotide substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting – For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1." The evidence for this variant shows: SpliceAI delta = 0, CADD = 0.66, indicating no predicted impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting – Variant found in case with an alternate molecular basis for disease." The evidence for this variant shows: no such case reports. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting – Reputable source reports variant as benign without primary evidence." The evidence for this variant shows: ClinVar includes Likely Benign but with primary evidence lacking. However, VCEP discourages PP5/BP6. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting – A synonymous variant at or beyond -21/+7 with no predicted splicing impact." The evidence for this variant shows: it is a synonymous G963= and SpliceAI delta = 0. Therefore, this criterion is applied at Supporting strength.