About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.4002-26_4002-25insCT, p.?
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen MSH6 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
The grpmax filtering allele frequency in gnomAD v4.1 is 0.0241 (2.41%) in the East Asian population, which exceeds the VCEP BA1 threshold of ≥0.0022 (0.22%). The variant has a total v4.1 allele frequency of 0.00185 (186/100,732 alleles) and is not known to be a founder pathogenic variant. This frequency is incompatible with MSH6-associated Lynch syndrome prevalence.
BP4Supporting
BP4 · supporting
For intronic variants, the VCEP BP4_Supporting rule is met when SpliceAI predicts no splicing impact with a delta score ≤ 0.1. SpliceAI predicts no significant splice impact for this variant (max delta = 0.02).
BP7Supporting
BP7 · supporting
NM_000179.3:c.4002-26_4002-25insCT is an intronic variant located at positions -26 and -25 relative to the exon 10 boundary, which is beyond -21 from the splice acceptor site. This satisfies the VCEP BP7 rule for intronic variants at or beyond -21/+7.
Recorded classification: Benign
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting benign, BP7 supporting benign; maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
186 / 100,732 alleles
gnomAD v4.1: 186 / 100,732 alleles. Recorded AF 0.00184648. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00067623; MAF= 0.06762%, 112/165624 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00684678; MAF= 0.68468%, 74/10808 alleles, homozygotes = 0); grpmax FAF= 0.00636889.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Benign.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH6 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 13 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000179.3:c.4002-26_4002-25insCT is present in gnomAD v4.1 at a grpmax filtering allele frequency of 2.41% in the East Asian population, exceeding the InSiGHT MSH6 VCEP BA1 stand-alone benign threshold of 0.22%. This population frequency is incompatible with a pathogenic role in Lynch syndrome.
SpliceAI predicts no splicing impact (max delta = 0.02), meeting the VCEP BP4_Supporting criterion for intronic variants.
The variant is located at intronic positions -26/-25, satisfying the VCEP BP7_Supporting criterion for intronic variants at or beyond -21/+7.
No pathogenic evidence criteria are met: PVS1 is not applicable (deep intronic, no null-allele evidence); PM2 is not met (gnomAD v4.1 AF = 0.185%); PP3 is not met (SpliceAI delta 0.02 < 0.2); and no functional, segregation, de novo, or tumor phenotype data support pathogenicity.
No criteria match.
Met · 3
BA1 Stand aloneThe grpmax filtering allele frequency in gnomAD v4.1 is 0.0241 (2.41%) in the East Asian population, which exceeds the VCEP BA1 threshold of ≥0.0022 (0.22%). The variant has a total v4.1 allele frequency of 0.00185 (186/100,732 alleles) and is not known to be a founder pathogenic variant. This frequency is incompatible with MSH6-associated Lynch syndrome prevalence. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.0240982 (2.41%) in East Asian population.
- gnomAD v4.1 total AF = 0.00184648 (186/100
- 732 alleles
- 0 homozygotes).
- VCEP BA1 threshold = ≥0.0022 (0.22%).
Sources
BP4 SupportingFor intronic variants, the VCEP BP4_Supporting rule is met when SpliceAI predicts no splicing impact with a delta score ≤ 0.1. SpliceAI predicts no significant splice impact for this variant (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02
- ≤ 0.1 threshold for BP4_Supporting.
Sources
BP7 SupportingNM_000179.3:c.4002-26_4002-25insCT is an intronic variant located at positions -26 and -25 relative to the exon 10 boundary, which is beyond -21 from the splice acceptor site. This satisfies the VCEP BP7 rule for intronic variants at or beyond -21/+7. Details ▾Hide ▴
Evidence considered
- Variant is an intronic insertion at c.4002-26_4002-25 (intron 9)
- located beyond the -21 intronic boundary specified by the VCEP BP7 rule.
Sources
Not met · 13 · evaluated, threshold not reached
PVS1 NM_000179.3:c.4002-26_4002-25insCT is a deep intronic 2-bp insertion in intron 9, 26-25 nucleotides upstream of exon 10. It does not introduce a premature termination codon, is not located at a canonical ±1,2 splice site, and no RNA-based evidence of a splicing aberration leading to a null allele is available. The variant does not meet any of the VCEP PVS1 strength rules for MSH6. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02
- indicating no predicted splicing impact.
- VCEP PVS1 rules require PTC ≤ codon 1341
- canonical ±1
- 2 splice disruption
- large genomic alteration
- or confirmed mRNA splicing aberration. None apply to this intronic insertion.
Still missing
- No RNA splicing assay data from patient-derived samples available for this variant.
- Functional impact of deep intronic insertion at -26/-25 on transcript processing is unknown.
Sources
PS1 PS1 requires either the same amino acid change as a known pathogenic missense variant, or a variant at the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse SpliceAI prediction. This intronic insertion does not encode an amino acid change, and no pathogenic variant has been established at the c.4002-26/-25 position. Details ▾Hide ▴
Evidence considered
- Variant is an intronic insertion
- not a missense substitution.
- No known pathogenic splice variant at the same intronic nucleotide position.
Sources
PS2 No de novo observations of NM_000179.3:c.4002-26_4002-25insCT have been reported in ClinVar, the published literature, or public databases. The VCEP PS2 point-based system cannot be applied. Details ▾Hide ▴
Evidence considered
- Literature and database searches identified zero de novo occurrences.
Still missing
- No de novo reports available.
PS3 No functional studies (MMR activity assays, protein expression, or splicing reporter assays) directly testing NM_000179.3:c.4002-26_4002-25insCT were identified. The VCEP PS3 rules require calibrated functional assay odds for pathogenicity or MMR function defect evidence, none of which is available for this variant. Details ▾Hide ▴
Evidence considered
- No functional data for this specific variant found in ClinVar
- LOVD
- PubMed
- or VCEP functional assay documentation.
Still missing
- No functional characterization of this intronic insertion has been performed.
PM2 The VCEP PM2 (Supporting) threshold requires absent or extremely rare allele frequency (<0.00002; <1 in 50,000 alleles) in gnomAD v4. NM_000179.3:c.4002-26_4002-25insCT is present in gnomAD v4.1 at an allele frequency of 0.00185 (186/100,732 alleles, ~9.3 per 50,000), which exceeds the PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total allele frequency = 0.00184648 (186/100
- 732 alleles).
- VCEP PM2_Supporting threshold = <0.00002.
Sources
PP1 No cosegregation data are available for NM_000179.3:c.4002-26_4002-25insCT. No pedigrees with combined Bayes likelihood ratio have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified in the literature or databases.
Still missing
- No cosegregation data available.
PP3 For intronic variants, the VCEP PP3_Supporting rule requires SpliceAI delta score ≥ 0.2 for a predicted splice defect at non-canonical nucleotides. SpliceAI predicts no splicing impact (max delta = 0.02), which is well below the 0.2 threshold. The HCI prior is not applicable as this is not a missense substitution. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02
- below the 0.2 threshold required for PP3_Supporting.
Sources
PP4 No tumor MSI or immunohistochemistry data are available for patients carrying NM_000179.3:c.4002-26_4002-25insCT. The VCEP PP4 rules require MSI-H colorectal/endometrial tumors and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data identified.
Still missing
- No MSI or IHC data from variant carriers.
BS1 The VCEP BS1 (Strong) threshold is grpmax FAF ≥ 0.00022 and < 0.0022 (0.022-0.22%). The observed grpmax FAF of 0.0241 (2.41%) exceeds the BS1 upper bound. This frequency range is instead captured by BA1 (Stand Alone). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.0240982
- exceeding the BS1 range (0.00022-0.0022).
Sources
BS2 BS2 requires co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. No such observation has been reported. Details ▾Hide ▴
Evidence considered
- No trans-co-occurrence data identified.
Still missing
- No co-occurrence observations available.
BS3 No calibrated functional assay data or laboratory-based mRNA splicing assays are available for NM_000179.3:c.4002-26_4002-25insCT. While SpliceAI predicts no splicing impact (delta 0.02), the VCEP BS3 rule requires laboratory assays conducted with nonsense-mediated decay inhibition, not in silico predictions alone. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.02 suggests no splicing impact
- but in silico prediction does not satisfy the VCEP BS3 requirement for laboratory-based functional evidence.
Still missing
- No laboratory RNA splicing or MMR functional assay data for this variant.
Sources
BS4 No pedigrees demonstrating lack of cosegregation with disease have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies available.
BP5 BP5 requires MSS colorectal/endometrial tumors or BRAF V600E/MLH1 methylation with MSI-H/MLH1 loss. No tumor phenotype data are available for carriers of this variant. Details ▾Hide ▴
Evidence considered
- No tumor data available.
Still missing
- No tumor MSI
- IHC
- BRAF
- or MLH1 methylation data from variant carriers.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PS4 Not Applicable for this gene. Details ▾Hide ▴
Sources
PM1 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PM1 Not Applicable for this gene. Details ▾Hide ▴
Sources
PM4 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PM4 Not Applicable for this gene. Details ▾Hide ▴
Sources
PM5 N/APM5 applies only to missense variants at an amino acid residue where a different missense change has been classified as pathogenic. This is an intronic insertion and does not encode an amino acid change. Details ▾Hide ▴
PM6 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PM6 Not Applicable for this gene. Details ▾Hide ▴
Sources
PP2 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PP2 Not Applicable (missense variant in a gene with low rate of benign missense changes does not apply). Details ▾Hide ▴
Sources
PP5 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares PP5 Not Applicable for this gene. Details ▾Hide ▴
Sources
BP1 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares BP1 Not Applicable (missense variant in a gene where only loss of function causes disease is not applicable). Details ▾Hide ▴
Sources
BP2 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares BP2 Not Applicable for this gene. Details ▾Hide ▴
Sources
BP3 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares BP3 Not Applicable (in-frame deletions/insertions in a repetitive region without a known function is not used). Details ▾Hide ▴
Sources
BP6 VCEPThe InSiGHT MSH6 VCEP v2.0.0 declares BP6 Not Applicable as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
PS5 N/APS5 is not included in the InSiGHT MSH6 VCEP v2.0.0 criteria set and is not applicable under this framework. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.4002-26_4002-25insCT
- Protein (HGVS p.)
- NP_000170.1:p.?
- GRCh38
- chr2:47806752 T>TTC
- GRCh37
- chr2:48033891 T>TTC
- ClinVar
- 1280853
Gene diagram
Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.3. Select a row to find it on the plot.
MSH6NM_000179.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MSH6
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
186 / 100,732 alleles
AF 0.00185 · 0 homozygotes · FAF 0.0241
gnomAD v2.1
112 / 165,624 alleles
AF 0.000676 · 0 homozygotes · FAF 0.00637
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.0018 · 186 / 100,732 alleles · 0 hom · FAF 0.024
| East Asian105 / 3,682 | 0.029 |
| Middle Eastern2 / 292 | 0.0068 |
| Remaining individuals15 / 3,058 | 0.0049 |
| South Asian14 / 5,426 | 0.0026 |
| Admixed American9 / 8,196 | 0.0011 |
| African/African American9 / 10,398 | 0.00087 |
| European (non-Finnish)31 / 62,992 | 0.00049 |
| European (Finnish)1 / 4,598 | 0.00022 |
0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00068 · 112 / 165,624 alleles · 0 hom · FAF 0.0064
| East Asian74 / 10,808 | 0.0068 |
| African/African American17 / 13,474 | 0.0013 |
| Remaining individuals2 / 4,378 | 0.00046 |
| Admixed American9 / 21,612 | 0.00042 |
| South Asian5 / 19,860 | 0.00025 |
| European (Finnish)1 / 11,954 | 8.4e-05 |
| European (non-Finnish)4 / 76,120 | 5.3e-05 |
0 alternate alleles recorded in 1 other group: Ashkenazi Jewish.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00184648; MAF= 0.18465%, 186/100732 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0285171; MAF= 2.85171%, 105/3682 alleles, homozygotes = 0); grpmax FAF= 0.0240982.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00067623; MAF= 0.06762%, 112/165624 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00684678; MAF= 0.68468%, 74/10808 alleles, homozygotes = 0); grpmax FAF= 0.00636889.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor intronic variants, the VCEP BP4_Supporting rule is met when SpliceAI predicts no splicing impact with a delta score ≤ 0.1. SpliceAI predicts no significant splice impact for this variant (max delta = 0.02). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02
- ≤ 0.1 threshold for BP4_Supporting.
Sources
BP7 SupportingNM_000179.3:c.4002-26_4002-25insCT is an intronic variant located at positions -26 and -25 relative to the exon 10 boundary, which is beyond -21 from the splice acceptor site. This satisfies the VCEP BP7 rule for intronic variants at or beyond -21/+7. Details ▾Hide ▴
Evidence considered
- Variant is an intronic insertion at c.4002-26_4002-25 (intron 9)
- located beyond the -21 intronic boundary specified by the VCEP BP7 rule.
Sources
PP3 For intronic variants, the VCEP PP3_Supporting rule requires SpliceAI delta score ≥ 0.2 for a predicted splice defect at non-canonical nucleotides. SpliceAI predicts no splicing impact (max delta = 0.02), which is well below the 0.2 threshold. The HCI prior is not applicable as this is not a missense substitution. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02
- below the 0.2 threshold required for PP3_Supporting.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
186 / 100,732 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1578294885
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1280853/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48033891-T-TTC?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47806752-T-TTC?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.4002…
- OncoKB ↗www.oncokb.org/gene/MSH6/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.4002-26_4002-25insCT
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00184648; MAF= 0.18465%, 186/100732 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0285171; MAF= 2.85171%, 105/3682 alleles, homozygotes = 0); grpmax FAF= 0.0240982.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00067623; MAF= 0.06762%, 112/165624 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00684678; MAF= 0.68468%, 74/10808 alleles, homozygotes = 0); grpmax FAF= 0.00636889.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1280853)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).