MSH6 c.3557-6_3573del, p.?
NM_000179.3:c.3557-6_3573del
Variant of Uncertain Significance (VUS)
This intronic/exonic deletion in MSH6 is absent from population databases (PM2_Supporting) and predicted by SpliceAI to disrupt splicing (PP3_Supporting). No other evidence supports pathogenicity or benign impact. Per VCEP rules, PVS1 is not met for non-canonical splice sites. Therefore, the variant remains classified as VUS.
ACMG/AMP Criteria Applied
PM2
PP3
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.3557-6_3573del
Protein Change
?
Location
Exon 6-7
(Exon 6 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.3557-6_3573del
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding 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 a deletion from c.3557-6 into the exon, outside the canonical ±1/2 splice sites. Therefore, this criterion is not applied because the variant does not affect the canonical splice dinucleotides covered by PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change as a previously established pathogenic variant (not a splice defect)." The evidence for this variant shows an intronic/exonic deletion predicted to affect splicing, not a missense change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no data on de novo status for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity > 18.7." No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS4 is: "The prevalence of the variant in affected individuals is significantly increased 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/finding for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." This variant is an intronic/exonic deletion outside known functional motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting: 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.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." MSH6-associated Lynch syndrome is autosomal dominant, and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions." This variant affects splicing and its impact on protein length is not established. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change was classified as Pathogenic." This variant is not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." There are no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP1 is: "Co-segregation with disease in pedigree(s) with a combined likelihood ratio >2.08 (Supporting)." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in a gene with low rate of benign missense variation." This variant is predicted to affect splicing, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting: Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2." The evidence for this variant shows a SpliceAI delta score of 1.0 for acceptor loss. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP4 is: "Supporting: 1 CRC/Endometrial MSI-H tumor with loss of MMR protein expression consistent with variant location." No tumor phenotype data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic without available evidence." This variant is not reported in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone: GnomAD v4 allele frequency ≥0.22%." The variant is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS1 is: "Strong: GnomAD v4 allele frequency ≥0.022% and <0.22%." The variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS2 is: "Strong: Co-occurrence in trans with a known pathogenic variant in LS gene in a patient without CMMRD." No co-occurrence data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS3 is: "Strong: Calibrated functional assays show no functional impact." No functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: "Lack of co-segregation with disease in pedigree(s) with combined likelihood ratio <0.05." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in gene where only truncating variants cause disease." This variant affects splicing. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." No phasing or cis/trans data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame deletion in a repetitive region without known function." This variant affects splicing and is not an in-frame deletion in a repeat. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP4 is: "Computational evidence suggests no impact (SpliceAI delta ≤0.1)." SpliceAI delta is 1.0, indicating impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular basis for disease." No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign without evidence." The variant is not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP7 is: "Synonymous or intronic variant at or beyond –21/+7 with no splicing impact." This deletion overlaps –6/+? positions and is predicted to impact splicing. Therefore, this criterion is not applied.