MSH6 c.3173-12C>T, p.?
NM_000179.3:c.3173-12C>T
Likely Benign
The variant NM_000179.3:c.3173-12C>T in MSH6 is absent from population databases (PM2_Supporting), predicted to have no splicing impact (BP4_Supporting), and reported as benign by reputable sources (BP6_Supporting). No pathogenic evidence applies. The overall classification is Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
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.3173-12C>T
Protein Change
?
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.3173-12C>T
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
Likely Benign
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
6 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 (6 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: 0.80
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: 'Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD.' The evidence for this variant shows it is at c.3173-12, outside the canonical IVS±1 or ±2 splice sites. Therefore, this criterion is not applied at Not Applied strength because the variant does not occur at a position meeting the VCEP PVS1 rule.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 requires a predicted missense substitution encoding the same amino acid change as a known Pathogenic variant. The evidence for this variant shows no missense change. Therefore, this criterion is not applied at Not Applied strength because the variant is intronic and does not meet PS1 requirements.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires de novo occurrence with parental confirmation. The evidence for this variant shows no data on de novo status or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies showing a damaging effect. The evidence for this variant shows no functional characterization. Therefore, this criterion is not applied at Not Applied strength because functional data are not available.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals compared to controls (case–control data). The evidence for this variant shows no case–control data. Therefore, this criterion is not applied at Not Applied strength because case–control evidence is lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 pertains to variants located in mutational hot spots or well‐established functional domains without benign variation. The evidence for this variant shows it is intronic and not in a defined hotspot or functional domain. Therefore, this criterion is not applied at Not Applied strength.
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 evidence for this variant shows it is not present in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders when variants are observed in trans with a pathogenic variant. The evidence for this variant shows no data on trans observations in a recessive context. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in‐frame deletions/insertions. The evidence for this variant shows no protein change (intronic location). Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where other missense changes are pathogenic. The evidence for this variant shows no missense change. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. The evidence for this variant shows no de novo or parental data. Therefore, this criterion is not applied at Not Applied strength.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires co‐segregation with disease in multiple affected family members. The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense variation where such variants are common disease mechanism. The evidence for this variant shows it is intronic. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2.' The evidence for this variant shows a SpliceAI maximum delta score of 0.02. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not predict a splice defect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires tumor phenotype data (e.g., MSI-H, loss of MMR protein expression) consistent with Lynch syndrome. The evidence for this variant shows no tumor or IHC data. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports a variant as Pathogenic without available evidence. The evidence for this variant shows no such report. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires a GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022. The evidence for this variant shows it is absent in population databases. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires a GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022. The evidence for this variant shows it is absent in population databases. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires co‐occurrence in trans with a known pathogenic variant in LS cancers without CMMRD evidence. The evidence for this variant shows no such observation. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 Strong applies to calibrated functional assays showing no deleterious effect or intronic/synonymous variants with no mRNA aberration. The evidence for this variant shows no functional or mRNA assay data. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of co‐segregation with disease in families. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where loss‐of‐function is known mechanism of disease. The evidence for this variant shows it is intronic. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to variants observed in trans with a pathogenic variant in dominant disorders. The evidence for this variant shows no such observation. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions. The evidence for this variant shows it is a single‐nucleotide intronic change. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤ 0.1.' The evidence for this variant shows a SpliceAI maximum delta score of 0.02. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires tumors inconsistent with Lynch syndrome or specific tumor markers. The evidence for this variant shows no tumor data. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: 'Reputable source recently reports variant as benign but the evidence is not available for independent evaluation.' The evidence for this variant shows it is reported as Likely Benign by six clinical laboratories in ClinVar. Therefore, this criterion is applied at Supporting strength because a reputable source classifies it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'A synonymous or intronic variant at or beyond -21/+7 (5′/3′ exonic).' The evidence for this variant shows it is at c.3173-12, which is within -21 to -7 and not at or beyond the specified boundaries. Therefore, this criterion is not applied at Not Applied strength.