About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3602_3606delinsAA, p.(Leu1201_Met1202delinsGln)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000179.3:c.3602_3606delinsAA is absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). The variant is also absent from gnomAD v2.1 and gnomAD-Canada v1.0.
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; 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
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.
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 ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 1 met · 15 not met · 0 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
NM_000179.3:c.3602_3606delinsAA is an in-frame deletion-insertion in MSH6 exon 7, resulting in the substitution of leucine 1201 and methionine 1202 with a single glutamine residue (p.Leu1201_Met1202delinsGln).
This variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency <0.00002 (1 in 50,000 alleles).
The variant is absent from ClinVar with no submissions from any laboratory.
No functional data, segregation data, tumor phenotype data, or literature reports are available for this variant. The variant has not been tested in any MSH6 VCEP-calibrated functional assay.
PVS1 is not met because this in-frame delins does not introduce a premature termination codon and does not meet any PVS1 rule under the MSH6 VCEP specification (v2.0.0), which requires a nonsense, frameshift, or canonical splice variant.
With only PM2_Supporting met and no other criteria applicable, the variant is classified as a Variant of Uncertain Significance under the ClinGen InSiGHT MSH6 VCEP combination rules (v2.0.0).
No criteria match.
Met · 1
PM2 SupportingNM_000179.3:c.3602_3606delinsAA is absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). The variant is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0/0 alleles
- AF <0.00002)
- also absent from v2.1 and gnomAD-Canada
Sources
Not met · 15 · evaluated, threshold not reached
PVS1 NM_000179.3:c.3602_3606delinsAA is an in-frame deletion-insertion (5 bp deleted, 2 bp inserted; net -3 bp) resulting in p.(Leu1201_Met1202delinsGln). It does not introduce a premature termination codon, is not a frameshift or nonsense variant, and does not disrupt a canonical splice site. Under the ClinGen InSiGHT MSH6 VCEP specification (v2.0.0), PVS1 at any strength requires a nonsense/frameshift PTC ≤ codon 1341 (Very Strong) or between codons 1342-1360 (Moderate), a canonical ±1,2 splice variant, or an initiation codon variant. This in-frame delins does not meet any PVS1 rule. Details ▾Hide ▴
Evidence considered
- In-frame deletion-insertion
- no PTC introduced
- reading frame preserved
Sources
cspec ↗pvs1_variant_assessment
PS1 PS1 applies to missense substitutions encoding the same amino acid change as an established pathogenic variant, or to variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant. This variant is an in-frame delins, not a missense substitution, and does not involve a splice site. No applicable PS1 comparator exists. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- PS1 rules apply only to missense substitutions or splice-site variants
Sources
PS2 No de novo observations have been reported for this variant. The literature screen identified zero publications, and ClinVar contains no submissions for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available
- variant absent from ClinVar and literature
Still missing
- No clinical or research data available to assess de novo status
Sources
PS3 No functional data exists for NM_000179.3:c.3602_3606delinsAA. The variant is absent from the MSH6 VCEP-calibrated functional assays (Drost 2018/2020 CIMRA, Jia 2021/Scott 2022 saturation mutagenesis, Rath 2022, Thompson 2013, Morak 2019, Bouvet 2019). OncoKB reports unknown oncogenic effect with no variant-specific curated functional evidence. No published experimental characterization of this exact variant or a systematically characterized range that includes it was identified. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data in any calibrated MMR assay
- no published experimental functional evidence
Still missing
- No functional characterization of this variant in any experimental system
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data is available for this variant. No family studies or pedigrees have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No segregation data available in any source
Still missing
- No family or pedigree data available to assess co-segregation
Sources
PP3 Under the MSH6 VCEP, PP3 is applicable only to missense variants with HCI prior probability >0.68 or to non-canonical splice variants with SpliceAI delta ≥0.2. This variant is an in-frame delins and does not fall into either category. No REVEL, BayesDel, HCI prior, or SpliceAI scores are available for this variant type. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- PP3 framework does not apply to this variant class
- no in silico scores available
Sources
PP4 No tumor phenotype data is available for this variant. No MSI-H tumors with loss of MMR protein expression consistent with MSH6 have been reported in association with this variant in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No tumor MSI or IHC data available
Still missing
- No tumor phenotype data available for PP4 assessment
Sources
BA1 The variant is absent from gnomAD v4.1 with a grpmax filtering allele frequency of 0%, well below the MSH6 VCEP BA1 threshold of ≥0.0022 (0.22%). An allele frequency this low does not support a stand-alone benign classification. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- AF 0% does not meet BA1 threshold of ≥0.22%
Sources
BS1 The variant is absent from gnomAD v4.1. The MSH6 VCEP BS1 threshold is a grpmax filtering allele frequency of ≥0.00022 (0.022%) and <0.0022 (0.22%). The observed AF of 0% does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- AF 0% does not meet BS1 threshold of ≥0.022%
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 and without CMMRD features. No such cases have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available
Still missing
- No clinical data available to assess trans co-occurrence
Sources
BS3 No functional data demonstrating proficient MMR function for this variant. The variant has not been tested in any of the MSH6 VCEP-calibrated functional assays (CIMRA, saturation mutagenesis, cell survival, or splicing assays). Details ▾Hide ▴
Evidence considered
- No functional data available
- variant untested in calibrated MMR assays
Still missing
- No functional characterization to support or refute pathogenicity
Sources
vcep_functional_assay_svi_documentation_mmroncokb ↗
BS4 No segregation or lack-of-segregation data is available for this variant. No family pedigrees have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No pedigree data to assess co-segregation or lack thereof
Sources
BP4 Under the MSH6 VCEP, BP4 applies only to missense variants with HCI prior probability <0.11 or to intronic/synonymous variants with SpliceAI delta ≤0.1. This variant is an in-frame delins and does not fall into either category. No computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- Variant class (in-frame delins) not covered by BP4 rules
- no in silico scores available
Sources
BP5 No tumor data demonstrating MSS status or retained MMR protein expression inconsistent with the variant gene is available. No CRC or endometrial tumors have been reported in association with this variant. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available to assess BP5
Still missing
- No tumor MSS/IHC data available
Sources
PS5 No publications or ClinVar submissions associate NM_000179.3:c.3602_3606delinsAA with disease. The variant is absent from ClinVar and no literature reports were identified in the literature triage pass. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no publications found
Still missing
- No published clinical or research reports for this variant
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
PM5 N/APM5 under the MSH6 VCEP applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic or Likely Pathogenic. This variant is an in-frame delins, not a missense substitution, and is not eligible for classic same-residue PM5 assessment. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not a missense substitution
- PM5 framework does not apply
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0. Details ▾Hide ▴
Sources
BP7 N/ABP7 under the MSH6 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is an in-frame deletion-insertion in exon 7 and does not meet the BP7 criteria. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3602_3606delinsAA
- Protein (HGVS p.)
- NP_000170.1:p.(Leu1201_Met1202delinsGln)
- GRCh38
- chr2:47805663 TCATG>AA
- GRCh37
- chr2:48032802 TCATG>AA
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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Under the MSH6 VCEP, PP3 is applicable only to missense variants with HCI prior probability >0.68 or to non-canonical splice variants with SpliceAI delta ≥0.2. This variant is an in-frame delins and does not fall into either category. No REVEL, BayesDel, HCI prior, or SpliceAI scores are available for this variant type. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- PP3 framework does not apply to this variant class
- no in silico scores available
Sources
BP4 Under the MSH6 VCEP, BP4 applies only to missense variants with HCI prior probability <0.11 or to intronic/synonymous variants with SpliceAI delta ≤0.1. This variant is an in-frame delins and does not fall into either category. No computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- Variant class (in-frame delins) not covered by BP4 rules
- no in silico scores available
Sources
BP7 N/ABP7 under the MSH6 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is an in-frame deletion-insertion in exon 7 and does not meet the BP7 criteria. Details ▾Hide ▴
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.3602_3606delinsAA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48032802-TCATG-AA?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47805663-TCATG-AA?datase…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47805663-TCATG-AA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3602…
- OncoKB ↗www.oncokb.org/gene/MSH6/L1201_M1202delinsQ
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.3602_3606delinsAA
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
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.