About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3556+1G>C, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant affects the canonical +1 splice donor position of MSH6. The MSH6 VCEP PVS1 rule allows very strong evidence for IVS±1/2 variants when the predicted splice outcome disrupts the reading frame and is expected to undergo nonsense-mediated decay, and the affected donor corresponds to exon 6, whose skipping would be out of frame. SpliceAI also predicts a strong splice effect with a max delta score of 1.00, supporting disruption of normal splicing.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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 was evaluated deterministically with applied criteria: PM2 supporting, PVS1 very strong; no rule matched the adjudicated criteria.
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
2 / 1,607,140 alleles
gnomAD v4.1: 2 / 1,607,140 alleles. Recorded AF 1.24445e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 4 not met · 9 not assessed · 13 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 NM_000179.3:c.3556+1G>C (NP_000170.1:p.?) variant has been reported in ClinVar as Pathogenic by a single clinical laboratory.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002.
This canonical +1 splice-donor variant is predicted to disrupt splicing, with SpliceAI showing a maximum delta score of 1.00, and the MSH6 VCEP PVS1 framework supports very strong pathogenic evidence for canonical splice variants expected to cause a frameshifting transcript subject to nonsense-mediated decay.
No criteria match.
Met · 2
PVS1 Very strongThis variant affects the canonical +1 splice donor position of MSH6. The MSH6 VCEP PVS1 rule allows very strong evidence for IVS±1/2 variants when the predicted splice outcome disrupts the reading frame and is expected to undergo nonsense-mediated decay, and the affected donor corresponds to exon 6, whose skipping would be out of frame. SpliceAI also predicts a strong splice effect with a max delta score of 1.00, supporting disruption of normal splicing. Details ▾Hide ▴
Rule
MSH6 VCEP PVS1 very strong applies to IVS±1/2 variants when the predicted splicing defect disrupts the frame and is predicted to undergo NMD.
Evidence considered
- Canonical splice donor variant c.3556+1G>C
- MSH6 loss of function established in the VCEP framework
- Generic PVS1 scaffold marks a canonical splice variant and advises not to stack PP3
- SpliceAI max delta 1.00
Still missing
- Direct RNA confirmation would further define the exact aberrant transcript.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength. Details ▾Hide ▴
Rule
MSH6 VCEP PM2 applies at supporting strength for allele frequency <0.00002 in gnomAD v4.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 1.24445e-06 (2/1
- 607
- 140 alleles)
- MSH6 VCEP PM2 threshold <0.00002
Sources
Not met · 4 · evaluated, threshold not reached
BA1 The gnomAD v4.1 total allele frequency is 1.24445e-06 (0.00012%), which is below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%), so this frequency does not support a benign stand-alone classification. Details ▾Hide ▴
Rule
MSH6 VCEP BA1 requires gnomAD v4 grpmax filtering AF ≥0.0022.
Evidence considered
- gnomAD v4.1 total AF 1.24445e-06 (2/1
- 607
- 140 alleles)
- MSH6 VCEP BA1 threshold 0.0022
Sources
BS1 The highest observed gnomAD v4.1 population allele frequency is 1.60653e-05 (0.00161%) in Remaining individuals, which is below the BS1 range of 0.00022 to <0.0022, so the population data do not support BS1. Details ▾Hide ▴
Rule
MSH6 VCEP BS1 requires gnomAD v4 grpmax filtering AF ≥0.00022 and <0.0022.
Evidence considered
- gnomAD v4.1 best subpopulation AF 1.60653e-05 (1/62
- 246 alleles)
- MSH6 VCEP BS1 lower bound 0.00022
Sources
BP4 SpliceAI predicts a strong splice effect with a max delta score of 1.00, which is above the MSH6 VCEP BP4 no-impact threshold of 0.1 for intronic variants. A BayesDel score of 0.325996 is available, but it does not overcome the splice prediction evidence and does not satisfy the VCEP BP4 rule. Details ▾Hide ▴
Rule
MSH6 VCEP BP4 for intronic variants requires SpliceAI delta score ≤0.1 predicting no splicing impact.
Evidence considered
- SpliceAI max delta 1.00
- BayesDel score 0.325996
- MSH6 VCEP BP4 splice threshold ≤0.1
Sources
BP7 This intronic variant is at the +1 canonical splice donor position, not at or beyond the BP7 boundary of +7, so it does not meet the MSH6 VCEP BP7 rule. Details ▾Hide ▴
Rule
MSH6 VCEP BP7 applies to synonymous variants or intronic variants at or beyond -21/+7.
Evidence considered
- Variant nomenclature c.3556+1G>C
- MSH6 VCEP BP7 boundary intronic +7 or farther
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data were identified for this variant, so PS2 cannot be applied. Details ▾Hide ▴
Rule
MSH6 VCEP PS2 uses a points-based de novo framework.
Evidence considered
- No de novo evidence identified
Still missing
- Confirmed maternity/paternity and de novo occurrence data are needed.
Sources
PS3 No validated RNA study or calibrated functional assay was identified for this exact variant showing an abnormal MSH6 effect, so PS3 cannot be applied at this time. Details ▾Hide ▴
Rule
MSH6 VCEP PS3 requires calibrated pathogenic functional evidence, a flowchart-supported MMR function defect, or complete monoallelic loss of expression.
Evidence considered
- No qualifying pathogenic functional evidence identified
Still missing
- Variant-specific RNA or calibrated functional assay data are needed.
Sources
PM3 No data were identified showing this variant in trans with another MSH6 pathogenic or likely pathogenic variant in a proband meeting the VCEP PM3 framework, so PM3 was not applied. Details ▾Hide ▴
Rule
MSH6 VCEP PM3 uses a points-based framework for variants observed with another MMR variant in CMMRD-relevant settings.
Evidence considered
- No qualifying PM3 evidence identified
Still missing
- Co-occurrence
- phase
- and clinical CMMRD context would be needed.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified, so there is no Bayes likelihood ratio available to support PP1. Details ▾Hide ▴
Rule
MSH6 VCEP PP1 requires cosegregation with disease meeting Bayes LR thresholds.
Evidence considered
- No segregation evidence identified
Still missing
- Informative family segregation data are needed.
Sources
PP4 No microsatellite instability or mismatch repair immunohistochemistry data were identified for this variant, so the tumor phenotype-specific PP4 rule cannot be applied. Details ▾Hide ▴
Rule
MSH6 VCEP PP4 uses MSI-H and/or protein-expression evidence with strength based on the number of independent tumors.
Evidence considered
- No qualifying MSI/IHC evidence identified
Still missing
- MSI and/or MMR immunohistochemistry results are needed.
Sources
BS2 No evidence was identified showing this variant in trans with a known pathogenic MSH6 variant in an individual meeting the VCEP BS2 conditions and lacking evidence of CMMRD. Details ▾Hide ▴
Rule
MSH6 VCEP BS2 requires phase-confirmed in trans co-occurrence with a pathogenic variant under specified clinical conditions.
Evidence considered
- No qualifying in trans co-occurrence data identified
Still missing
- Phase-confirmed co-occurrence data with clinical context are needed.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No RNA or functional assay evidence was identified showing normal splicing or preserved MSH6 function for this variant, so BS3 cannot be applied. Details ▾Hide ▴
Rule
MSH6 VCEP BS3 requires calibrated benign functional evidence or RNA evidence showing no associated mRNA aberration.
Evidence considered
- No benign functional or RNA evidence identified
Still missing
- RNA studies or validated functional assays showing no damaging effect are needed.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
MSH6 VCEP BS4 requires lack of cosegregation meeting Bayes LR thresholds.
Evidence considered
- No non-segregation evidence identified
Still missing
- Informative family data showing lack of segregation are needed.
Sources
BP5 No tumor findings inconsistent with MSH6-related disease were identified, so BP5 was not applied. Details ▾Hide ▴
Rule
MSH6 VCEP BP5 requires multiple discordant tumor observations or specified MLH1-related findings.
Evidence considered
- No qualifying discordant tumor evidence identified
Still missing
- Multiple discordant tumor findings or qualifying MLH1 methylation/BRAF evidence would be needed.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is a canonical splice-donor change and no applicable same-amino-acid or same non-canonical splice-nucleotide comparator rule is available for PS1 in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
MSH6 VCEP PS1 applies to same-amino-acid missense substitutions or the same non-canonical splice nucleotide with similar or worse predicted impact.
Evidence considered
- Variant is a canonical +1 splice donor change
Sources
PS4 N/APS4 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PS4 as not applicable
Sources
PM1 N/APM1 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PM1 as not applicable
Sources
PM4 N/APM4 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PM4 as not applicable
Sources
PM5 N/APM5 is a missense-residue rule and is not applicable to this splice-donor variant. Details ▾Hide ▴
Rule
MSH6 VCEP PM5 applies to missense substitutions at residues with established pathogenic missense comparators.
Evidence considered
- Variant is a splice-donor change rather than a missense substitution
Sources
PM6 N/APM6 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PM6 as not applicable
Sources
PP2 N/APP2 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PP2 as not applicable
Sources
PP3 N/ASpliceAI predicts a splice effect with a max delta score of 1.00, but the MSH6 VCEP PP3 splice rule is limited to non-canonical splicing nucleotides, and the PVS1 framework for canonical ±1/2 splice variants states that PP3 should not be combined for the same splice-prediction evidence. A BayesDel score of 0.325996 is available but is not the operative VCEP rule for this canonical splice-donor variant. Details ▾Hide ▴
Rule
MSH6 VCEP PP3 splice use is limited to non-canonical splicing nucleotides with SpliceAI ≥0.2.
Evidence considered
- Canonical +1 splice donor variant
- SpliceAI max delta 1.00
- BayesDel score 0.325996
- VCEP instruction not to stack PP3 with PVS1 for canonical splice prediction evidence
Sources
PP5 N/APP5 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks PP5 as not applicable
Sources
BP1 N/ABP1 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks BP1 as not applicable
Sources
BP2 N/ABP2 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks BP2 as not applicable
Sources
BP3 N/ABP3 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks BP3 as not applicable
Sources
BP6 N/ABP6 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
Rule
Criterion not used by this VCEP.
Evidence considered
- MSH6 VCEP marks BP6 as not applicable
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3556+1G>C
- Protein (HGVS p.)
- NP_000170.1:p.?
- GRCh38
- chr2:47805028 G>C
- GRCh37
- chr2:48032167 G>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
—
Transcript span
—
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
2 / 1,607,140 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,607,140 alleles · 0 hom
| Remaining individuals1 / 62,246 | 1.6e-05 |
| European (non-Finnish)1 / 1,173,668 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24445e-06; MAF= 0.00012%, 2/1607140 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60653e-05; MAF= 0.00161%, 1/62246 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SpliceAI predicts a strong splice effect with a max delta score of 1.00, which is above the MSH6 VCEP BP4 no-impact threshold of 0.1 for intronic variants. A BayesDel score of 0.325996 is available, but it does not overcome the splice prediction evidence and does not satisfy the VCEP BP4 rule. Details ▾Hide ▴
Rule
MSH6 VCEP BP4 for intronic variants requires SpliceAI delta score ≤0.1 predicting no splicing impact.
Evidence considered
- SpliceAI max delta 1.00
- BayesDel score 0.325996
- MSH6 VCEP BP4 splice threshold ≤0.1
Sources
BP7 This intronic variant is at the +1 canonical splice donor position, not at or beyond the BP7 boundary of +7, so it does not meet the MSH6 VCEP BP7 rule. Details ▾Hide ▴
Rule
MSH6 VCEP BP7 applies to synonymous variants or intronic variants at or beyond -21/+7.
Evidence considered
- Variant nomenclature c.3556+1G>C
- MSH6 VCEP BP7 boundary intronic +7 or farther
Sources
PP3 N/ASpliceAI predicts a splice effect with a max delta score of 1.00, but the MSH6 VCEP PP3 splice rule is limited to non-canonical splicing nucleotides, and the PVS1 framework for canonical ±1/2 splice variants states that PP3 should not be combined for the same splice-prediction evidence. A BayesDel score of 0.325996 is available but is not the operative VCEP rule for this canonical splice-donor variant. Details ▾Hide ▴
Rule
MSH6 VCEP PP3 splice use is limited to non-canonical splicing nucleotides with SpliceAI ≥0.2.
Evidence considered
- Canonical +1 splice donor variant
- SpliceAI max delta 1.00
- BayesDel score 0.325996
- VCEP instruction not to stack PP3 with PVS1 for canonical splice prediction evidence
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.325996.
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
2 / 1,607,140 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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/variation/572617/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48032167-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47805028-G-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3556…
- OncoKB ↗www.oncokb.org/gene/MSH6/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.3556+1G%3EC
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= 1.24445e-06; MAF= 0.00012%, 2/1607140 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60653e-05; MAF= 0.00161%, 1/62246 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.325996.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).