MSH6 c.336C>A, p.Asn112Lys
NM_000179.3:c.336C>A
Variant of Uncertain Significance (VUS)
This MSH6 N112K variant remains a VUS. Only PM2_Supporting and BP4_Supporting are met (absent from population databases and benign in silico/splicing predictions), with no additional pathogenic or benign evidence sufficient for reclassification.
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.336C>A
Protein Change
N112K
Location
Exon 2
(Exon 2 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 112 in gene MSH6
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.336C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The MSH6 c.336C>A (p.Asn112Lys) variant has not been reported in individuals with MSH6-related conditions in the published literature. In a large scale breast cancer association study, this variant has been observed in at least one breast cancer case and not in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0000066 (1/152218 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as 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 112 in gene MSH6
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.17polyphen_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 Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6 ...". The evidence for this variant shows a missense change (N112K). Therefore, this criterion is not applied because the variant does not introduce a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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 N112K. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Very Strong ≥ 4 de novo points...". No de novo occurrence has been reported for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Strong: well-established functional studies supportive of a damaging effect on the gene or gene product.". No functional studies have been performed for N112K. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Statistical enrichment of variant in affected individuals compared to controls.". No case/control or segregation data are available. 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.". Residue N112 is not in a recognized hotspot or critical domain for MSH6. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.". The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because it meets the rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive inheritance. MSH6 is associated with autosomal dominant Lynch syndrome. 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 indels or stop-loss.". This variant is a missense change and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at amino acid residue where a different missense change was classified by this VCEP as Pathogenic...". No other pathogenic variant at residue 112 has been reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Unconfirmed de novo occurrences.". There is no report of de novo occurrence for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members.". No 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 a low rate of benign missense variation.". MSH6 has both truncating and missense pathogenic variants and is not constrained to missense only. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: Missense variant with HCI prior probability of pathogenicity >0.68 OR predicted splice defect with SpliceAI delta ≥0.2.". In silico tools and SpliceAI do not predict a damaging effect (SpliceAI max 0.02). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Phenotype highly specific for gene (e.g., multiple MSI-H tumors).". No tumor or MSI 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 records the variant as VUS/benign. 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 max filtering allele frequency ≥0.0022.". The variant is absent. 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 variant is absent. 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 such data exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Calibrated functional assays showing no impact.". No functional assays have been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation with disease in families.". 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 truncating variants cause disease.". Missense variants in MSH6 can be pathogenic. 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 pathogenic variant in dominant disorder.". No 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 indel in repetitive region without known function.". This is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Missense variant with HCI prior probability <0.11 OR SpliceAI delta score ≤0.1.". The evidence shows SpliceAI delta of 0.02 and predominantly benign in silico predictions. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in case with alternate molecular cause.". No such 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 without evidence.". ClinVar submissions are conflicting/uncertain. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: synonymous or intronic variant at or beyond -21/+7.". This variant is missense. Therefore, this criterion is not applied.