MSH6 c.3945G>T, p.Lys1315Asn
NM_000179.3:c.3945G>T
Variant of Uncertain Significance (VUS)
MSH6 c.3945G>T (p.K1315N) is extremely rare in controls (PM2_Supporting) and predicted benign by multiple in silico tools with no splicing impact (BP4_Supporting). No functional, segregation, or statistical case data are available, resulting in a classification of Variant of Uncertain Significance.
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.3945G>T
Protein Change
K1315N
Location
Exon 9
(Exon 9 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1315 in gene MSH6
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.3945G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000401%
Extremely Rare
Highest in Population
East Asian
0.00545%
Rare
Global: 0.000401%
East Asian: 0.00545%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249618Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000401%, 1/249618 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.00545%, 1/18342 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 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 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 1315 in gene MSH6
Functional Summary
The MSH6 K1315N variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.271
0.271
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
Benign:
CADD: 2.77polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
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...". The evidence for this variant shows it is a missense substitution (K1315N), not a null/truncating variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic...". No previously established pathogenic variant causes the same K1315N change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong ≥ 4 de novo points (disease-specific)...". No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong Calibrated functional assays with functional odds for Pathogenicity > 18.7...". No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Statistically significant increased prevalence in affected individuals compared to controls.". No case–control or statistical data exist. 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 functional domain without benign variation.". There is no evidence that K1315 lies in a known hotspot or critical domain. 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 dataset.". The variant has MAF = 0.00000401 (1/249,618 alleles), which is below the threshold. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Very Strong ≥ 4 points for recessive inheritance...". MSH6-related disease is autosomal dominant and there is no evidence of in trans observations. 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 non-repeat regions.". This is a missense variant without protein length alteration. 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 a residue where a different missense change was classified as Pathogenic...". No other pathogenic missense at residue 1315 is documented. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting 0.5 de novo points for presumed de novo variants...". No de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Strong co-segregation with disease in pedigrees...". No family segregation data are available. 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 low rate of benign missense variation and where missense is a common mechanism of disease.". There is insufficient data on gene-specific missense constraint. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Moderate Missense variant with HCI prior probability >0.81 or predicted splice defect with SpliceAI ≥0.2.". Computational predictors (CADD, PolyPhen-2, REVEL=0.27) and SpliceAI (max score 0.04) do not support a deleterious effect. 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, loss of MMR protein) consistent with gene location.". No tumor or MSI/MMR expression data are available. 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.". ClinVar submissions are conflicting (Likely benign and VUS). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%).". The observed frequency (0.00000401) is well below this threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022.". The variant frequency (0.00000401) is below 0.00022. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong co-occurrence in trans with a known pathogenic variant...". No co-occurrence data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong functional assays show no deleterious effect (Odds ≤ 0.05).". No functional assays have been conducted. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong lack of co-segregation with disease.". No segregation data are available. 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 where only LOF causes disease.". Missense is a known mechanism of pathogenicity in MSH6. 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 recessive disorder...". No relevant co-occurrence data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions without functional impact.". This variant is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Missense variant with HCI-prior probability <0.11 OR SpliceAI predicts no splicing impact with delta score ≤ 0.1.". SpliceAI maximum delta score is 0.04 and computational predictors are uniformly benign. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Strong tumor-based evidence inconsistent with gene effect...". No tumor phenotype data are available. 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.". ClinVar submissions are conflicting (Likely benign and VUS). Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting synonymous/intronic variant at or beyond defined splice region.". This is a missense substitution, not synonymous or intronic. Therefore, this criterion is not applied.