Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 4435 nt | 153–4235 |
| NM_000179.1 | Alternative | 4264 nt | 88–4170 |
| NM_000179.3 | MANE Select | 4265 nt | 90–4172 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.G289D variant (also known as c.866G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 866. The glycine at codon 289 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is well conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
"This variant has been reported in ClinVar as Benign (1 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The MSH6 G289D variant has not been functionally characterized. In vitro assays indicate that it does not demonstrate reduced mismatch repair activity compared to the wild-type protein, but its effect on MSH6 protein function remains unknown due to incomplete biochemical characterization.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 70 bp |
| Donor Loss (DL) | 0.0 | -145 bp |
| Acceptor Gain (AG) | 0.01 | -234 bp |
| Donor Gain (DG) | 0.0 | 418 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6...". The evidence for this variant shows it is a missense change (G289D) and does not introduce a stop codon or frameshift. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic." The evidence for this variant shows no previously established pathogenic variant encoding G289D. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong ≥4 de novo points; Strong 2–3 de novo points; Moderate 1 de novo point; Supporting 0.5 de novo points." The evidence for this variant shows no information on de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7; Moderate: functional odds >4.3 and ≤18.7." The evidence for this variant shows in vitro assays indicate no reduction in MMR activity. There is no evidence of a functional defect. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Statistically increased prevalence in affected individuals compared to controls." The evidence for this variant shows no case-control or prevalence data in affected individuals. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain without benign variation." The evidence for this variant shows no data placing codon 289 in a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4." The evidence for this variant shows a global MAF of 0.0092% (9.2×10⁻⁵), which exceeds the threshold. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows no data on trans occurrence and MSH6 is associated with dominant Lynch syndrome. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss." The evidence for this variant shows a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 (Moderate) is: "Missense change at an amino acid residue where a different missense change was classified as Pathogenic by this VCEP." The evidence for this variant shows no other pathogenic missense at residue 289. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows no gene-specific constraint data. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Moderate: HCI prior >0.81 OR predicted splice defect with SpliceAI δ≥0.2." The evidence for this variant shows SpliceAI δ=0.01 and no HCI prior data. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting: 1 CRC/Endometrial MSI-H tumor or loss of MMR expression consistent with variant." The evidence for this variant shows no tumor phenotype or MMR expression data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows conflicting ClinVar assertions (Benign, Likely Benign, VUS). Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: "GnomAD v4 filtering allele frequency ≥0.0022." The evidence for this variant shows a maximum allele frequency of 0.000194, below threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: "GnomAD v4 filtering allele frequency ≥0.00022 and <0.0022." The evidence for this variant shows 0.000092, below 0.00022. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Strong) is: "Co-occurrence in trans with a pathogenic variant in a patient without CMMRD." The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied.
BS3 (Supporting)
According to VCEP guidelines, the rule for BS3 (Supporting) is: "Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart." The evidence for this variant shows in vitro assays indicating no reduction in mismatch repair activity. Therefore, BS3 is applied at Supporting strength.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of co-segregation with disease." The evidence for this variant shows no segregation analysis. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows missense variants are known in MSH6. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant." The evidence for this variant shows no data on cis occurrence. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions." The evidence for this variant shows a missense change, not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variant with HCI-prior <0.11 OR SpliceAI predicts no splicing impact with δ≤0.1." The evidence for this variant shows SpliceAI δ=0.01. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 (Supporting) is: "Tumors with alternate etiology inconsistent with gene." The evidence for this variant shows no tumor or alternate cause data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows conflicting assertions in ClinVar. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variants at or beyond −21/+7 with no splicing impact." The evidence for this variant shows a missense change. Therefore, this criterion is not applied.