About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3312del, p.(Phe1104LeufsTer11)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_000179.3:c.3312del is a frameshift deletion that introduces a premature termination codon at codon 1104 (p.Phe1104LeufsTer11). Per the ClinGen InSiGHT MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 qualify for PVS1_VeryStrong.
PM2Supporting
PM2 · supporting
NM_000179.3:c.3312del is present in gnomAD v4.1 at an extremely low allele frequency (AF = 6.20e-07; 1/1,614,052 alleles; 0 homozygotes). Per the MSH6 VCEP v2.0.0, variants absent or with allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 meet PM2_Supporting. The variant's AF (6.2e-07) is well below this threshold.
PP5Supporting
PP5 · supporting
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
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 Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.
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
1 / 1,614,052 alleles
gnomAD v4.1: 1 / 1,614,052 alleles. Recorded AF 6.19559e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
6 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
12 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52275040, n = 12 times).
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.
29 criteria with recorded statuses: 3 met · 2 not met · 8 not assessed · 16 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.3312del (p.Phe1104LeufsTer11) is a frameshift deletion in exon 5 of MSH6 predicted to introduce a premature termination codon at codon 1104, well within the VCEP threshold of codon 1341 for PVS1_VeryStrong.
This variant is extremely rare in population databases, with a single heterozygous observation in gnomAD v4.1 (AF = 6.20e-07; 1/1,614,052 alleles) and absent from gnomAD v2.1, meeting PM2_Supporting per MSH6 VCEP thresholds (AF <0.00002).
This variant has been classified as Pathogenic by the InSiGHT expert panel in ClinVar (Variation ID: 89371) and by six clinical laboratories. The ClinVar record cites PMIDs 16360201, 18269114, 20487569, and 27601186; however, full-text confirmation of variant-specific mention could not be verified for these papers, and PP5 is not applicable per VCEP guidance.
No de novo observations (PS2), calibrated functional assay data (PS3), segregation data (PP1/BS4), or tumor phenotype data (PP4/BP5) were identified in the literature for this specific variant.
Applying the MSH6 VCEP v2.0.0 combination rules: PVS1_VeryStrong alone meets Rule 1 (>=1 PVS1_VeryStrong), yielding a classification of Pathogenic.
No criteria match.
Met · 3
PVS1 Very strongNM_000179.3:c.3312del is a frameshift deletion that introduces a premature termination codon at codon 1104 (p.Phe1104LeufsTer11). Per the ClinGen InSiGHT MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 qualify for PVS1_VeryStrong. Details ▾Hide ▴
Evidence considered
- VCEP MSH6 v2.0.0 PVS1 rule: frameshift introducing PTC <= codon 1341 in MSH6 yields PVS1_VeryStrong
- Variant creates frameshift at codon 1104 with termination at codon 1114
- well within the <=1341 threshold
Sources
PM2 SupportingNM_000179.3:c.3312del is present in gnomAD v4.1 at an extremely low allele frequency (AF = 6.20e-07; 1/1,614,052 alleles; 0 homozygotes). Per the MSH6 VCEP v2.0.0, variants absent or with allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 meet PM2_Supporting. The variant's AF (6.2e-07) is well below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 6.19559e-07 (1/1
- 614
- 052 alleles
- 0 homozygotes)
- gnomAD v2.1: absent
- MSH6 VCEP PM2 threshold: <0.00002
Sources
Not met · 2 · evaluated, threshold not reached
BA1 The MSH6 VCEP BA1 criterion requires a gnomAD v4 Grpmax filtering allele frequency >=0.0022 (0.22%). NM_000179.3:c.3312del has an AF of 6.20e-07 in gnomAD v4.1 (1/1,614,052 alleles), far below the BA1 threshold. The variant is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 6.19559e-07 (far below BA1 threshold of 0.0022)
- gnomAD v2.1: absent
Sources
BS1 The MSH6 VCEP BS1 criterion requires a gnomAD v4 Grpmax filtering allele frequency >=0.00022 (0.022%). NM_000179.3:c.3312del has an AF of 6.20e-07 in gnomAD v4.1, which is well below the 0.022% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 6.19559e-07 (far below BS1 threshold of 0.00022)
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observation data were identified for NM_000179.3:c.3312del. The VCEP MSH6 PS2 criterion requires de novo points from confirmed de novo occurrences with parental testing. No published de novo reports or segregation data confirming de novo status for this variant were found in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
- No de novo observations identified in literature or ClinVar for this variant
PS3 No calibrated functional assay data were identified for NM_000179.3:c.3312del in the VCEP MMR functional assay documentation spreadsheet. The VCEP PS3 criterion requires functional odds for pathogenicity from calibrated assays. OncoKB annotates this variant as Likely Oncogenic (Likely Loss-of-function) in a somatic context, but this does not constitute calibrated germline functional evidence per VCEP standards. Details ▾Hide ▴
Evidence considered
- VCEP Functional-assay-SVI-documentation-MMR.xlsx: variant not listed
- OncoKB: Likely Oncogenic / Likely Loss-of-function (somatic context only)
Still missing
- No calibrated germline functional assay data for this specific variant
PP1 No co-segregation data (Bayes Likelihood Ratio from pedigree analysis) were identified for NM_000179.3:c.3312del. The MSH6 VCEP requires formal segregation analysis using the COOL tool to compute combined Bayes LR thresholds (>2.08 for Supporting, >4.3 for Moderate, >18.7 for Strong). No pedigrees with this variant were available in the evidence. Details ▾Hide ▴
Still missing
- No co-segregation pedigree data or Bayes LR values available for this variant
PP4 No tumor phenotype data (MSI-H status, MMR IHC, or loss of protein expression) were identified for patients carrying NM_000179.3:c.3312del. The MSH6 VCEP PP4 criterion requires independent CRC/Endometrial MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. No tumor-level evidence was found in the literature or ClinVar submissions for this specific variant. Details ▾Hide ▴
Still missing
- No MSI/IHC tumor phenotype data for patients with this variant
BS2 No evidence of co-occurrence in trans with a known pathogenic sequence variant in MSH6 was identified for this variant. The MSH6 VCEP BS2 criterion requires confirmed phase (parental testing) demonstrating in trans co-occurrence with a known pathogenic MSH6 variant in a patient with CRC after age 45 (or other LS cancer above median onset age) without CMMRD features. Details ▾Hide ▴
Still missing
- No in trans co-occurrence data with phased pathogenic variants
BS3 No calibrated functional assay data supporting a benign effect were identified for NM_000179.3:c.3312del. The VCEP MMR functional assay documentation spreadsheet does not list this variant, and no literature was identified reporting functional evidence of normal MMR activity for this specific frameshift variant. Details ▾Hide ▴
Evidence considered
- VCEP Functional-assay-SVI-documentation-MMR.xlsx: variant not listed in any calibrated assay
Still missing
- No functional assay data demonstrating normal function for this variant
BS4 No co-segregation data were available to evaluate lack of co-segregation with disease. The MSH6 VCEP BS4 criterion requires a combined Bayes Likelihood Ratio <0.05 (Strong) or between 0.05-0.48 (Supporting) from formal pedigree analysis. Details ▾Hide ▴
Still missing
- No segregation data for absence of co-segregation analysis
BP5 No tumor phenotype data supporting a benign interpretation were identified for NM_000179.3:c.3312del. The MSH6 VCEP BP5 criterion requires CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation with MSI-H/MLH1 loss. No such tumor-level data were available. Details ▾Hide ▴
Still missing
- No tumor MSS/IHC data for patients with this variant to support benign interpretation
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 per the MSH6 VCEP applies to predicted missense substitutions encoding the same amino acid change as an established pathogenic variant, or variants affecting the same non-canonical splice nucleotide as a pathogenic splice variant. NM_000179.3:c.3312del is a frameshift deletion, not a missense or splice variant. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPThe MSH6 VCEP v2.0.0 explicitly marks PS4 as Not Applicable for this gene. Details ▾Hide ▴
Sources
PM1 VCEPThe MSH6 VCEP v2.0.0 explicitly marks PM1 as Not Applicable for this gene. Details ▾Hide ▴
Sources
PM3 N/ATrivially not applicable per user directive (skip instruction). Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPThe MSH6 VCEP v2.0.0 explicitly marks PM4 as Not Applicable for this gene. Details ▾Hide ▴
Sources
PM5 N/APM5 per the MSH6 VCEP applies to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic/Likely Pathogenic. NM_000179.3:c.3312del is a frameshift deletion, not a missense variant. The pm5_candidates module confirmed the variant is not eligible for classic same-residue missense PM5 analysis. Details ▾Hide ▴
Sources
pm5_candidates
PM6 VCEPThe MSH6 VCEP v2.0.0 explicitly marks PM6 as Not Applicable for this gene. Details ▾Hide ▴
Sources
PP2 VCEPThe MSH6 VCEP v2.0.0 explicitly marks PP2 as Not Applicable for this gene. Details ▾Hide ▴
Sources
PP3 N/APP3 per the MSH6 VCEP applies to missense variants (with HCI prior probability thresholds) or non-canonical splice variants (with SpliceAI delta score >=0.2). NM_000179.3:c.3312del is a frameshift deletion. Neither REVEL/BayesDel scores nor HCI prior probabilities are available for deletion variants. SpliceAI predicts no splice impact (max delta = 0.00). The VCEP also notes PVS1 should not be combined with PP3 for the same molecular evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (no predicted splice impact)
- Variant is a frameshift deletion
- not eligible for HCI prior lookup
Sources
BP1 VCEPThe MSH6 VCEP v2.0.0 explicitly marks BP1 as Not Applicable for this gene. Details ▾Hide ▴
Sources
BP2 VCEPThe MSH6 VCEP v2.0.0 explicitly marks BP2 as Not Applicable for this gene. Details ▾Hide ▴
Sources
BP3 VCEPThe MSH6 VCEP v2.0.0 explicitly marks BP3 as Not Applicable for this gene. Details ▾Hide ▴
Sources
BP4 N/ABP4 per the MSH6 VCEP applies to missense variants with HCI prior probability <0.11, or intronic/synonymous variants with SpliceAI delta <=0.1. NM_000179.3:c.3312del is a frameshift deletion and does not fall within either applicable category. SpliceAI predicts no splicing impact (max delta = 0.00), but the criterion does not apply to coding frameshift variants. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- Variant type (frameshift deletion) is not eligible for BP4 per VCEP rules
Sources
BP6 VCEPThe MSH6 VCEP v2.0.0 explicitly marks BP6 as Not Applicable. The ClinGen SVI VCEP Review Committee recommends against using this criterion. Details ▾Hide ▴
Sources
BP7 N/ABP7 per the MSH6 VCEP applies to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). NM_000179.3:c.3312del is a coding frameshift deletion in exon 5; it is neither synonymous nor intronic. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). The pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, and PP1-PP5. The equivalent criterion for source-based pathogenicity evidence is PP5, which the MSH6 VCEP explicitly marks as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3312del
- Protein (HGVS p.)
- NP_000170.1:p.(Phe1104LeufsTer11)
- GRCh38
- chr2:47803552 CT>C
- GRCh37
- chr2:48030691 CT>C
- ClinVar
- 89371
- COSMIC
- COSV52275040
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
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in MSH6
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,614,052 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,052 alleles · 0 hom
| European (non-Finnish)1 / 1,180,034 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19559e-07; MAF= 0.00006%, 1/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47433e-07; MAF= 0.00008%, 1/1180034 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 per the MSH6 VCEP applies to missense variants (with HCI prior probability thresholds) or non-canonical splice variants (with SpliceAI delta score >=0.2). NM_000179.3:c.3312del is a frameshift deletion. Neither REVEL/BayesDel scores nor HCI prior probabilities are available for deletion variants. SpliceAI predicts no splice impact (max delta = 0.00). The VCEP also notes PVS1 should not be combined with PP3 for the same molecular evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (no predicted splice impact)
- Variant is a frameshift deletion
- not eligible for HCI prior lookup
Sources
BP4 N/ABP4 per the MSH6 VCEP applies to missense variants with HCI prior probability <0.11, or intronic/synonymous variants with SpliceAI delta <=0.1. NM_000179.3:c.3312del is a frameshift deletion and does not fall within either applicable category. SpliceAI predicts no splicing impact (max delta = 0.00), but the criterion does not apply to coding frameshift variants. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- Variant type (frameshift deletion) is not eligible for BP4 per VCEP rules
Sources
BP7 N/ABP7 per the MSH6 VCEP applies to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). NM_000179.3:c.3312del is a coding frameshift deletion in exon 5; it is neither synonymous nor intronic. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Thompson BA et al. · 2014No paper-specific finding is recorded.
-
PMID 1651234 ↗Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities.No paper-specific finding is recorded.
-
PMID 22810696 ↗Comprehensive molecular characterization of human colon and rectal cancer.No paper-specific finding is recorded.
-
PMID 24755471 ↗Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.No paper-specific finding is recorded.
-
PMID 9111312 ↗Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition.No paper-specific finding is recorded.
-
PMID 9564049 ↗hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha.No paper-specific finding is recorded.
-
PMID 9822680 ↗Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,052 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
6 Pathogenic
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/variation/89371/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48030691-CT-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47803552-CT-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3312…
- OncoKB ↗www.oncokb.org/gene/MSH6/F1104Lfs*11
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124985693
- 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
This variant is present in gnomAD v4.1 (AF= 6.19559e-07; MAF= 0.00006%, 1/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47433e-07; MAF= 0.00008%, 1/1180034 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89371)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52275040, n = 12 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.