About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.4002-17T>C, p.?
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada. Its observed population frequency is therefore below the MSH6 PM2 threshold of less than 0.00002 (fewer than 1 in 50,000 alleles), supporting rarity.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04. This is below the MSH6 BP4 threshold of less than or equal to 0.1 and supports no predicted splicing effect.
Recorded classification: Not classified
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 Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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: 2 met · 5 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MSH6 c.4002-17T>C (NP_000170.1:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada, supporting rarity below the MSH6 PM2 threshold of less than 0.00002.
SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, which is below the MSH6 BP4 threshold of less than or equal to 0.1 and below the PP3 threshold of greater than or equal to 0.2 for non-canonical splice variants.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada. Its observed population frequency is therefore below the MSH6 PM2 threshold of less than 0.00002 (fewer than 1 in 50,000 alleles), supporting rarity. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1: absent
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
- MSH6 PM2 threshold: <0.00002
Sources
BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04. This is below the MSH6 BP4 threshold of less than or equal to 0.1 and supports no predicted splicing effect. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1.
Evidence considered
- SpliceAI max delta score: 0.04
- MSH6 BP4 threshold for intronic/synonymous variants: <=0.1
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 Although loss of function is an established disease mechanism for MSH6, this variant is a non-canonical intronic change at c.4002-17 and does not fall within the default PVS1 null-variant categories. No patient RNA evidence showing a confirmed splice defect was identified, so PVS1 is not met. Details ▾Hide ▴
Rule
PVS1 in MSH6 applies to qualifying null variants or to variants with mRNA evidence showing a qualifying splice aberration.
Evidence considered
- MSH6 LoF mechanism supported
- Variant is non-canonical intronic
- Generic PVS1 scaffold: not a default null-variant bucket
Still missing
- Constitutional RNA evidence demonstrating a qualifying splice defect
Sources
PP3 SpliceAI does not support a predicted splice defect for this non-canonical intronic variant. The maximum delta score is 0.04, which is below the MSH6 PP3 threshold of greater than or equal to 0.2. Details ▾Hide ▴
Rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2.
Evidence considered
- SpliceAI max delta score: 0.04
- MSH6 PP3 threshold for non-canonical splice variants: >=0.2
Sources
BA1 This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BA1 threshold of filtering allele frequency greater than or equal to 0.0022 (0.22%). Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1: absent
- MSH6 BA1 threshold: >=0.0022
Sources
BS1 This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BS1 frequency range of greater than or equal to 0.00022 and less than 0.0022. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1: absent
- MSH6 BS1 range: >=0.00022 and <0.0022
Sources
BP7 This is an intronic variant at c.4002-17, which is 17 nucleotides from the exon boundary and does not meet the MSH6 BP7 distance requirement for variants at or beyond -21 or +7. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
- Variant position: c.4002-17
- MSH6 BP7 distance threshold: at or beyond -21/+7
Sources
Not assessed · 10 · no assessment recorded
PS1 No pathogenic or likely pathogenic comparator affecting the same non-canonical splice nucleotide was identified in the available evidence, so PS1 could not be applied. Details ▾Hide ▴
Rule
Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic or Likely Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Evidence considered
- ClinVar: absent
- No comparator evidence identified
Still missing
- Confirmed pathogenic or likely pathogenic comparator at the same non-canonical splice nucleotide with similar or worse splicing prediction
Sources
PS2 No de novo data were identified for this variant, so PS2 could not be assessed. Details ▾Hide ▴
Rule
De novo points-based criterion.
Evidence considered
- No de novo evidence identified
Still missing
- Confirmed de novo occurrence data with parental testing
Sources
PS3 No calibrated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 could not be assessed. Details ▾Hide ▴
Rule
Calibrated functional assays or qualifying MMR functional assay flowchart evidence showing a damaging effect.
Evidence considered
- No functional or RNA evidence identified
- No PMID-backed studies identified
Still missing
- Validated damaging functional study
- RNA study showing abnormal splicing or monoallelic loss of expression
Sources
PM3 No data were identified showing this variant in trans with another pathogenic MSH6 variant in a constitutional mismatch repair deficiency setting, so PM3 could not be assessed. Details ▾Hide ▴
Rule
PM3 in MSH6 is a points-based criterion for qualifying observations in trans.
Evidence considered
- No qualifying PM3 observations identified
Still missing
- Confirmed in trans observations with a pathogenic MSH6 variant
- Case-level CMMRD phenotypic data
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Rule
Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >2.08 and <=4.3 for Supporting, >4.3 and <=18.7 for Moderate, or >18.7 in >=2 families for Strong.
Evidence considered
- No segregation evidence identified
Still missing
- Pedigree data with segregation likelihood ratio
Sources
PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry data were identified, so PP4 could not be assessed. Details ▾Hide ▴
Rule
1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers or tumor genome and/or loss of MMR protein expression consistent with the variant location.
Evidence considered
- No tumor phenotype data identified
Still missing
- MSI testing results
- MMR immunohistochemistry results
Sources
BS2 No co-occurrence data in trans with a known pathogenic MSH6 variant in an older individual without features of constitutional mismatch repair deficiency were identified, so BS2 could not be assessed. Details ▾Hide ▴
Rule
Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS), and who has no previous or current evidence of clinical manifestations of CMMRD.
Evidence considered
- No qualifying co-occurrence evidence identified
Still missing
- Phase-confirmed co-occurrence data
- Clinical data addressing CMMRD features
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No variant-specific RNA or functional assay data showing normal splicing or retained function were identified, so BS3 could not be assessed. Details ▾Hide ▴
Rule
Synonymous substitutions and intronic variants with no associated mRNA aberration as determined by laboratory assays conducted with nonsense-mediated decay inhibition, or calibrated functional assays with functional odds for pathogenicity <=0.05.
Evidence considered
- No functional or RNA evidence identified
- No PMID-backed studies identified
Still missing
- RNA study with nonsense-mediated decay inhibition
- Validated functional assay showing no damaging effect
Sources
BS4 No non-segregation data were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Rule
Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio <0.48.
Evidence considered
- No non-segregation evidence identified
Still missing
- Pedigree data showing lack of co-segregation
Sources
BP5 No tumor data showing microsatellite-stable disease, retained mismatch repair protein expression, or gene-inconsistent loss of mismatch repair proteins were identified, so BP5 could not be assessed. Details ▾Hide ▴
Rule
Tumor-based benign evidence criterion for MSS/retained or gene-inconsistent MMR protein expression, or BRAF V600E/MLH1 methylation in relevant settings.
Evidence considered
- No qualifying tumor-based benign evidence identified
Still missing
- Tumor MSI results
- Tumor MMR immunohistochemistry results
- BRAF V600E or MLH1 methylation data if relevant
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
PM1 VCEPPM1 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
PM4 VCEPPM4 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
PM5 N/AThe MSH6 PM5 rule is a classic same-residue missense criterion. This variant is intronic and not missense-like, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- PM5 candidate review: variant not eligible for classic same-residue missense PM5
Sources
pm5_candidatescspec ↗
PM6 VCEPPM6 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
PP2 VCEPPP2 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
PP5 VCEPPP5 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
BP1 VCEPBP1 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
BP2 VCEPBP2 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
BP6 VCEPBP6 is not used in the MSH6 expert-panel framework. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.4002-17T>C
- Protein (HGVS p.)
- NP_000170.1:p.?
- GRCh38
- chr2:47806762 T>C
- GRCh37
- chr2:48033901 T>C
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04. This is below the MSH6 BP4 threshold of less than or equal to 0.1 and supports no predicted splicing effect. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1.
Evidence considered
- SpliceAI max delta score: 0.04
- MSH6 BP4 threshold for intronic/synonymous variants: <=0.1
Sources
PP3 SpliceAI does not support a predicted splice defect for this non-canonical intronic variant. The maximum delta score is 0.04, which is below the MSH6 PP3 threshold of greater than or equal to 0.2. Details ▾Hide ▴
Rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2.
Evidence considered
- SpliceAI max delta score: 0.04
- MSH6 PP3 threshold for non-canonical splice variants: >=0.2
Sources
BP7 This is an intronic variant at c.4002-17, which is 17 nucleotides from the exon boundary and does not meet the MSH6 BP7 distance requirement for variants at or beyond -21 or +7. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
- Variant position: c.4002-17
- MSH6 BP7 distance threshold: at or beyond -21/+7
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000179.3%3Ac.4002-17T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48033901-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47806762-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47806762-T-C
- 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.4002-17T%3EC
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).