About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.4T>A, p.(Ser2Thr)
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 and gnomAD v2.1. Under the MSH6 VCEP rule, absence or an allele frequency below 0.00002 in gnomAD v4 supports PM2 at supporting strength, so this criterion is met.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
For MSH6 missense variants, the VCEP uses the HCI prior probability for BP4. This variant has an HCI prior probability of 0.0038, which is below the BP4 threshold of 0.11, supporting a benign computational interpretation. REVEL is 0.405 and BayesDel is -0.114406, and these do not override the MSH6-specific HCI prior rule.
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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 11 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.4T>A (p.Ser2Thr) 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 and gnomAD v2.1, which meets the MSH6 VCEP PM2 threshold for supporting evidence because the observed allele frequency is below 0.00002.
For this MSH6 missense variant, the HCI prior probability is 0.0038, below the BP4 threshold of 0.11 and consistent with benign computational evidence; REVEL is 0.405 and BayesDel is -0.114406.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Under the MSH6 VCEP rule, absence or an allele frequency below 0.00002 in gnomAD v4 supports PM2 at supporting strength, so this criterion is met. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- MSH6 VCEP PM2 threshold is <0.00002 in gnomAD v4
Sources
BP4 SupportingFor MSH6 missense variants, the VCEP uses the HCI prior probability for BP4. This variant has an HCI prior probability of 0.0038, which is below the BP4 threshold of 0.11, supporting a benign computational interpretation. REVEL is 0.405 and BayesDel is -0.114406, and these do not override the MSH6-specific HCI prior rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability of pathogenicity <0.11.
Evidence considered
- HCI prior probability 0.0038
- REVEL score 0.405
- BayesDel score -0.114406
- MSH6 VCEP missense BP4 threshold is HCI prior <0.11
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is a missense change, NM_000179.3:c.4T>A (p.Ser2Thr), and does not alter the MSH6 initiation codon. The MSH6 VCEP PVS1 rules are intended for truncating variants, qualifying splice defects, exon-level genomic losses, or initiation codon variants, so this variant does not meet PVS1. Details ▾Hide ▴
Rule
MSH6 VCEP PVS1 applies to qualifying loss-of-function or initiation codon variants, not this missense substitution.
Evidence considered
- Protein consequence p.(Ser2Thr)
- Generic PVS1 scaffold marked this variant outside default null-variant buckets
- MSH6 VCEP PVS1 rule includes initiation codon variants
- but c.4T>A is outside codon 1
Sources
PP3 For MSH6 missense variants, the VCEP uses the HCI prior probability. This variant has an HCI prior probability of 0.0038, which is well below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI shows a max delta score of 0.27, but the MSH6 splice PP3 rule is intended for non-canonical splicing nucleotides, and this exonic missense variant does not meet that rule. Details ▾Hide ▴
Rule
Missense PP3 requires HCI prior >0.68; splice PP3 requires a non-canonical splicing nucleotide with SpliceAI >=0.2.
Evidence considered
- HCI prior probability 0.0038
- SpliceAI max delta score 0.27
- REVEL score 0.405
- BayesDel score -0.114406
Sources
BA1 This variant is absent from gnomAD v4.1, so it is below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%). BA1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.0022.
Evidence considered
- Absent from gnomAD v4.1
- BA1 threshold is >=0.0022
Sources
BS1 This variant is absent from gnomAD v4.1, so it is below the MSH6 VCEP BS1 range of 0.00022 to <0.0022. BS1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.00022 and <0.0022.
Evidence considered
- Absent from gnomAD v4.1
- BS1 range is >=0.00022 and <0.0022
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified that a different nucleotide change causing the same p.Ser2Thr amino acid substitution has been previously established as pathogenic or likely pathogenic by this VCEP. Details ▾Hide ▴
Rule
Same amino acid change previously established as pathogenic/likely pathogenic by this VCEP.
Evidence considered
- MSH6 VCEP PS1 requires an established same amino acid change with a different nucleotide change
Still missing
- No same-amino-acid pathogenic comparator variant was identified in the retrieved evidence.
Sources
PS2 No confirmed de novo occurrence with appropriate parental confirmation was identified for this variant. Details ▾Hide ▴
PS3 No calibrated functional study showing a damaging effect for this specific variant was identified. Details ▾Hide ▴
Rule
Requires calibrated damaging functional evidence or MMR defect per VCEP flowchart.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
- No PMIDs were retrieved
Still missing
- No variant-specific abnormal MMR functional assay data were identified.
Sources
PM3 No confirmed in trans observations with a pathogenic MSH6 variant in an appropriate constitutional mismatch repair deficiency context were identified. Details ▾Hide ▴
Rule
Use point-based in trans framework when qualifying observations are available.
Evidence considered
- No CMMRD or in trans case data were retrieved
Still missing
- No phase-confirmed in trans data were identified.
Sources
PM5 No evidence was identified that a different missense change at codon 2 has been established by this VCEP as pathogenic or likely pathogenic on the protein level. Details ▾Hide ▴
Rule
Different pathogenic/likely pathogenic missense change at same residue, with PP3 prerequisite.
Evidence considered
- MSH6 VCEP PM5 requires a different pathogenic or likely pathogenic missense change at the same residue
Still missing
- No qualifying codon-level pathogenic comparator variant was identified.
Sources
PP1 No segregation data were identified for this variant, so a Bayes likelihood ratio for co-segregation could not be calculated. Details ▾Hide ▴
PP4 No tumor microsatellite instability results or mismatch repair immunohistochemistry findings were identified to support an MSH6-consistent Lynch syndrome tumor phenotype. Details ▾Hide ▴
Rule
Requires qualifying MSI-H tumor and/or MMR protein loss evidence.
Evidence considered
- No phenotype-specific tumor evidence was retrieved
Still missing
- No MSI or IHC tumor data were identified.
Sources
BS2 No evidence was identified showing this variant in trans with a known pathogenic MSH6 variant in an individual whose clinical findings argue against constitutional mismatch repair deficiency. Details ▾Hide ▴
Rule
Requires qualifying in trans co-occurrence with clinical features arguing against CMMRD.
Evidence considered
- No qualifying co-occurrence data were retrieved
Still missing
- No phase-confirmed in trans observation with the required clinical context was identified.
Sources
BS3 No calibrated functional study showing retained MSH6 function for this variant was identified. Details ▾Hide ▴
Rule
Requires calibrated benign functional evidence or variant-specific proficient function per VCEP flowchart.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
- No PMIDs were retrieved
Still missing
- No variant-specific benign functional evidence was identified.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
BP5 No tumor findings were identified that would argue against this variant being the cause of an MSH6-related disorder. Details ▾Hide ▴
Rule
Requires qualifying tumor evidence inconsistent with the gene or syndrome mechanism.
Evidence considered
- No MSS or inconsistent MMR protein expression data were retrieved
Still missing
- No qualifying contradictory tumor data were identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 N/APS4 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PS4 as not applicable
Sources
PM1 N/APM1 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PM1 as not applicable
Sources
PM4 N/APM4 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PM4 as not applicable
Sources
PM6 N/APM6 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PM6 as not applicable
Sources
PP2 N/APP2 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PP2 as not applicable
Sources
PP5 N/APP5 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks PP5 as not applicable
Sources
BP1 N/ABP1 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks BP1 as not applicable
Sources
BP2 N/ABP2 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks BP2 as not applicable
Sources
BP3 N/ABP3 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks BP3 as not applicable
Sources
BP6 N/ABP6 is not used in this MSH6 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- MSH6 VCEP marks BP6 as not applicable
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant only.
Evidence considered
- Protein consequence is p.(Ser2Thr)
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.4T>A
- Protein (HGVS p.)
- NP_000170.1:p.(Ser2Thr)
- GRCh38
- chr2:47783237 T>A
- GRCh37
- chr2:48010376 T>A
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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor MSH6 missense variants, the VCEP uses the HCI prior probability for BP4. This variant has an HCI prior probability of 0.0038, which is below the BP4 threshold of 0.11, supporting a benign computational interpretation. REVEL is 0.405 and BayesDel is -0.114406, and these do not override the MSH6-specific HCI prior rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability of pathogenicity <0.11.
Evidence considered
- HCI prior probability 0.0038
- REVEL score 0.405
- BayesDel score -0.114406
- MSH6 VCEP missense BP4 threshold is HCI prior <0.11
Sources
PP3 For MSH6 missense variants, the VCEP uses the HCI prior probability. This variant has an HCI prior probability of 0.0038, which is well below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI shows a max delta score of 0.27, but the MSH6 splice PP3 rule is intended for non-canonical splicing nucleotides, and this exonic missense variant does not meet that rule. Details ▾Hide ▴
Rule
Missense PP3 requires HCI prior >0.68; splice PP3 requires a non-canonical splicing nucleotide with SpliceAI >=0.2.
Evidence considered
- HCI prior probability 0.0038
- SpliceAI max delta score 0.27
- REVEL score 0.405
- BayesDel score -0.114406
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant only.
Evidence considered
- Protein consequence is p.(Ser2Thr)
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.405. BayesDel score = -0.114406. HCI prior probability for pathogenicity = 0.0038. MAPP score = 3.15. Custom PP2 score = 0.243.
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
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB 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.4T%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48010376-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47783237-T-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.4T%3…
- OncoKB ↗www.oncokb.org/gene/MSH6/S2T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.4T%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.405. BayesDel score = -0.114406. HCI prior probability for pathogenicity = 0.0038. MAPP score = 3.15. Custom PP2 score = 0.243.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.