About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3261del, p.(Phe1088SerfsTer2)
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
This variant is a frameshift deletion predicted to produce p.(Phe1088SerfsTer2). Under the MSH6 VCEP specification, nonsense/frameshift variants introducing a premature termination codon at or before codon 1341 meet PVS1 at Very Strong strength; this variant truncates the protein at codon 1088 and loss of function is an established disease mechanism for MSH6.
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases. In gnomAD v4.1, the allele frequency is 1.42855e-05 (23/1610026 alleles) with grpmax FAF 7.65e-06, which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), and it is absent from gnomAD-Canada v1.0.
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
23 / 1,610,026 alleles
gnomAD v4.1: 23 / 1,610,026 alleles. Recorded AF 1.42855e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.42412e-05; MAF= 0.00142%, 4/280876 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.68804e-05; MAF= 0.00969%, 1/10322 alleles, homozygotes = 0).
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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
32 reported laboratory submissions
31 Pathogenic · 1 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
132 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52273658, n = 132 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.
28 criteria with recorded statuses: 3 met · 2 not met · 9 not assessed · 14 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.3261del (NP_000170.1:p.(Phe1088SerfsTer2)) variant has been observed in somatic cancers in COSMIC (COSV52273658, n=132) and has been reported in ClinVar as Pathogenic, including an expert-panel assertion.
This variant is present at extremely low frequency in population databases, with gnomAD v4.1 allele frequency 1.42855e-05 (23/1610026 alleles; grpmax FAF 7.65e-06), which is below the MSH6 VCEP PM2 threshold of 0.00002, and it is absent from gnomAD-Canada v1.0.
This frameshift deletion is predicted to truncate MSH6 at codon 1088, and the active MSH6 VCEP specification applies PVS1 at Very Strong strength to nonsense or frameshift variants introducing a premature termination codon at or before codon 1341.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a frameshift deletion predicted to produce p.(Phe1088SerfsTer2). Under the MSH6 VCEP specification, nonsense/frameshift variants introducing a premature termination codon at or before codon 1341 meet PVS1 at Very Strong strength; this variant truncates the protein at codon 1088 and loss of function is an established disease mechanism for MSH6. Details ▾Hide ▴
Rule
MSH6 VCEP PVS1 Very Strong for nonsense/frameshift variants introducing a premature termination codon at or before codon 1341.
Evidence considered
- NM_000179.3:c.3261del predicts NP_000170.1:p.(Phe1088SerfsTer2)
- MSH6 VCEP PVS1 Very Strong applies to nonsense/frameshift variants with PTC at or before codon 1341
- Loss of function is an established MSH6 disease mechanism in the active VCEP framework
Sources
PM2 SupportingThis variant is present at extremely low frequency in population databases. In gnomAD v4.1, the allele frequency is 1.42855e-05 (23/1610026 alleles) with grpmax FAF 7.65e-06, which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), and it is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Rule
MSH6 VCEP PM2 Supporting when allele frequency in gnomAD v4 is <0.00002.
Evidence considered
- gnomAD v4.1 total AF 1.42855e-05
- 23/1610026 alleles
- 0 homozygotes
- grpmax FAF 7.65e-06
- Absent from gnomAD-Canada v1.0
- gnomAD v2.1 total AF 1.42412e-05
- 4/280876 alleles
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%). Details ▾Hide ▴
Rule
MSH6 VCEP BA1 requires gnomAD v4 grpmax filtering allele frequency >=0.0022.
Evidence considered
- gnomAD v4.1 total AF 1.42855e-05
- grpmax FAF 7.65e-06
Sources
BS1 This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is below the MSH6 VCEP BS1 range of 0.00022 to <0.0022. Details ▾Hide ▴
Rule
MSH6 VCEP BS1 requires gnomAD v4 grpmax filtering allele frequency >=0.00022 and <0.0022.
Evidence considered
- gnomAD v4.1 grpmax FAF 7.65e-06
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with verified parentage was identified. Details ▾Hide ▴
Rule
MSH6 VCEP PS2 requires de novo points based on phenotype specificity and parentage confirmation.
Still missing
- Parental testing and de novo scoring data were not identified.
Sources
PS3 No directly reviewed calibrated functional assay or RNA evidence demonstrating an abnormal MSH6 effect for this exact variant was identified for PS3 assignment. Details ▾Hide ▴
Rule
MSH6 VCEP PS3 requires calibrated pathogenic functional evidence or specified defective assay results.
Evidence considered
- OncoKB links variant-specific literature leads but does not by itself establish PS3
Still missing
- No variant-specific pathogenic functional assay result was identified.
- Curated literature leads require direct review before PS3 can be assigned.
Sources
cspec ↗vcep_functional_assay_flowchartvcep_functional_assay_svi_documentation_mmroncokb ↗PMID:15837969 ↗PMID:21674763 ↗
PM3 No phase-confirmed biallelic observations or PM3 point-based evidence were identified. Details ▾Hide ▴
Rule
MSH6 VCEP PM3 requires point-based evidence from biallelic observations.
Still missing
- No PM3 point-scoring observations were identified.
- Phase-confirmed in trans data were not identified.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation dataset with a combined Bayes likelihood ratio meeting PP1 thresholds was identified. Details ▾Hide ▴
Rule
MSH6 VCEP PP1 requires co-segregation with disease reaching the specified Bayes likelihood ratio threshold.
Still missing
- Pedigree-level segregation data were not identified.
- A Bayes likelihood ratio for segregation was not available.
Sources
PP4 No directly reviewed tumor MSI or mismatch-repair immunohistochemistry data specific enough to assign PP4 were identified. Details ▾Hide ▴
Rule
MSH6 VCEP PP4 requires specified MSI-H and/or MMR protein loss evidence.
Still missing
- Variant-specific MSI or IHC evidence was not identified in a form sufficient for VCEP PP4 strength assignment.
Sources
BS2 No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusion requirements was identified. Details ▾Hide ▴
Rule
MSH6 VCEP BS2 requires confirmed in trans co-occurrence with a pathogenic variant in an appropriately phenotyped individual.
Still missing
- Phase-confirmed in trans co-occurrence data were not identified.
- Clinical information needed to exclude CMMRD manifestations was not identified.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No directly reviewed calibrated functional assay or RNA study demonstrating normal MSH6 function for this variant was identified. Details ▾Hide ▴
Rule
MSH6 VCEP BS3 requires calibrated benign functional evidence or specified normal RNA/protein assay results.
Still missing
- No variant-specific benign functional assay result was identified.
- No RNA study showing no aberrant effect was identified.
Sources
cspec ↗vcep_functional_assay_flowchartvcep_functional_assay_svi_documentation_mmrPMID:15837969 ↗PMID:21674763 ↗
BS4 No segregation dataset with a combined Bayes likelihood ratio supporting lack of co-segregation was identified. Details ▾Hide ▴
Rule
MSH6 VCEP BS4 requires lack of co-segregation with disease reaching the specified Bayes likelihood ratio threshold.
Still missing
- Pedigree-level segregation data were not identified.
- A Bayes likelihood ratio for non-segregation was not available.
Sources
BP5 No tumor series showing repeated mismatch between the tumor phenotype and the gene harboring this variant was identified. Details ▾Hide ▴
Rule
MSH6 VCEP BP5 requires specified discordant tumor evidence.
Still missing
- Tumor-level MSS/IHC discordance evidence was not identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 was not applied because this variant is not a missense substitution or a non-canonical splice variant eligible for the MSH6 VCEP PS1 rule. Details ▾Hide ▴
Rule
MSH6 VCEP PS1 applies to specified missense or non-canonical splice nucleotide contexts.
Evidence considered
- Frameshift coding deletion
Sources
PS4 VCEPPS4 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
PM1 VCEPPM1 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
PM4 VCEPPM4 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
PM5 N/APM5 was not applied because the MSH6 VCEP PM5 rule is a classic same-residue missense rule, and this variant is a frameshift deletion rather than a missense change. Details ▾Hide ▴
Rule
MSH6 VCEP PM5 applies only to qualifying missense variants at the same residue.
Evidence considered
- PM5 candidate review found the variant is not eligible for classic same-residue missense PM5
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
PP3 N/APP3 was not applied because the MSH6 VCEP PP3 rule is limited to missense variants with qualifying HCI prior scores or non-canonical splice variants with SpliceAI >=0.2. This variant is a frameshift deletion, and the observed SpliceAI max delta score is 0.04. Details ▾Hide ▴
Rule
MSH6 VCEP PP3 applies only to specified missense or non-canonical splice variant classes.
Evidence considered
- Frameshift variant
- not a missense or non-canonical splice variant
- SpliceAI max delta score 0.04
- No HCI prior is available because the variant is not a substitution
Sources
BP1 VCEPBP1 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
BP4 N/ABP4 was not applied because the MSH6 VCEP BP4 rule is limited to missense variants with HCI prior probability <0.11 or to synonymous/intronic variants with SpliceAI <=0.1. This variant is a frameshift deletion, so those computational rules do not apply. Details ▾Hide ▴
Rule
MSH6 VCEP BP4 applies only to specified missense, synonymous, or intronic variant classes.
Evidence considered
- Frameshift variant
- not a missense
- synonymous
- or intronic variant
- SpliceAI max delta score 0.04
Sources
BP6 VCEPBP6 is not used in the MSH6 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 was not applied because this variant is not a synonymous or sufficiently deep intronic change. Details ▾Hide ▴
Rule
MSH6 VCEP BP7 applies to synonymous or specified intronic variants.
Evidence considered
- Frameshift coding deletion
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3261del
- Protein (HGVS p.)
- NP_000170.1:p.(Phe1088SerfsTer2)
- GRCh38
- chr2:47803500 AC>A
- GRCh37
- chr2:48030639 AC>A
- ClinVar
- 89363
- COSMIC
- COSV52273658
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
23 / 1,610,026 alleles
AF 1.43e-05 · 0 homozygotes · FAF 7.65e-06
gnomAD v2.1
4 / 280,876 alleles
AF 1.42e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.4e-05 · 23 / 1,610,026 alleles · 0 hom · FAF 7.6e-06
| European (Finnish)4 / 63,712 | 6.3e-05 |
| East Asian1 / 44,802 | 2.2e-05 |
| Remaining individuals1 / 62,362 | 1.6e-05 |
| African/African American1 / 74,238 | 1.3e-05 |
| European (non-Finnish)15 / 1,177,722 | 1.3e-05 |
| South Asian1 / 90,950 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: Admixed American, Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 1.4e-05 · 4 / 280,876 alleles · 0 hom
| Ashkenazi Jewish1 / 10,322 | 9.7e-05 |
| African/African American1 / 24,758 | 4e-05 |
| European (Finnish)1 / 25,028 | 4e-05 |
| European (non-Finnish)1 / 127,934 | 7.8e-06 |
0 alternate alleles recorded in 4 other groups: Admixed American, East Asian, Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.42855e-05; MAF= 0.00143%, 23/1610026 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 6.27825e-05; MAF= 0.00628%, 4/63712 alleles, homozygotes = 0); grpmax FAF= 7.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.42412e-05; MAF= 0.00142%, 4/280876 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.68804e-05; MAF= 0.00969%, 1/10322 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 was not applied because the MSH6 VCEP PP3 rule is limited to missense variants with qualifying HCI prior scores or non-canonical splice variants with SpliceAI >=0.2. This variant is a frameshift deletion, and the observed SpliceAI max delta score is 0.04. Details ▾Hide ▴
Rule
MSH6 VCEP PP3 applies only to specified missense or non-canonical splice variant classes.
Evidence considered
- Frameshift variant
- not a missense or non-canonical splice variant
- SpliceAI max delta score 0.04
- No HCI prior is available because the variant is not a substitution
Sources
BP4 N/ABP4 was not applied because the MSH6 VCEP BP4 rule is limited to missense variants with HCI prior probability <0.11 or to synonymous/intronic variants with SpliceAI <=0.1. This variant is a frameshift deletion, so those computational rules do not apply. Details ▾Hide ▴
Rule
MSH6 VCEP BP4 applies only to specified missense, synonymous, or intronic variant classes.
Evidence considered
- Frameshift variant
- not a missense
- synonymous
- or intronic variant
- SpliceAI max delta score 0.04
Sources
BP7 N/ABP7 was not applied because this variant is not a synonymous or sufficiently deep intronic change. Details ▾Hide ▴
Rule
MSH6 VCEP BP7 applies to synonymous or specified intronic variants.
Evidence considered
- Frameshift coding deletion
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
10 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
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PMID 21674763 ↗High-grade brain tumors in siblings with biallelic MSH6 mutations.No paper-specific finding is recorded.
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PMID 15837969 ↗Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?No paper-specific finding is recorded.
-
PMID 15236168 ↗Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.Hendriks YM et al. · 2004No paper-specific finding is recorded.
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PMID 15483016 ↗Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.Plaschke J et al. · 2004No paper-specific finding is recorded.
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PMID 17117178 ↗Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.Kets CM et al. · 2006No paper-specific finding is recorded.
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PMID 19526325 ↗Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.Berginc G et al. · 2009No paper-specific finding is recorded.
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PMID 20007843 ↗Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients.Dymerska D et al. · 2010No paper-specific finding is recorded.
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PMID 20028993 ↗Risks of Lynch syndrome cancers for MSH6 mutation carriers.Baglietto L et al. · 2010No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 32720330 ↗Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.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
23 / 1,610,026 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
31 Pathogenic · 1 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/89363/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48030639-AC-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47803500-AC-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47803500-AC-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3261…
- OncoKB ↗www.oncokb.org/gene/MSH6/F1088Sfs*2
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124980552
- 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= 1.42855e-05; MAF= 0.00143%, 23/1610026 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 6.27825e-05; MAF= 0.00628%, 4/63712 alleles, homozygotes = 0); grpmax FAF= 7.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.42412e-05; MAF= 0.00142%, 4/280876 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.68804e-05; MAF= 0.00969%, 1/10322 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89363)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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; COSV52273658, n = 132 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.