About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.1796G>A, p.(Gly599Glu)
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. 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
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the InSiGHT MSH6 VCEP threshold for PM2_Supporting (allele frequency < 0.00002, i.e., <1 in 50,000 alleles).
PP3Moderate
PP3 · moderate
The HCI prior probability for pathogenicity is 0.9346, which exceeds the InSiGHT MSH6 VCEP threshold of >0.81 for PP3_Moderate in missense variants.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
In progress — evidence not uploaded yet.
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, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant NM_000179.2:c.1796G>A (p.Gly599Glu) in MSH6 is a missense substitution absent from all gnomAD population databases (PM2_Supporting).
In silico prediction supports a deleterious effect: HCI prior probability for pathogenicity is 0.9346, meeting the MSH6 VCEP threshold for PP3_Moderate (>0.81). REVEL score is 0.807, also consistent with a damaging prediction.
No functional assay data, segregation data, or tumor phenotype data are available for this variant. The variant has not been reported in ClinVar with expert panel review (currently Uncertain significance, 1-star).
Multiple VCEP criteria are marked Not Applicable (PP5, BP6, PM1, PP2, PS4, PM6, BP1, BP2) as per the InSiGHT MSH6 VCEP v2.0 framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the InSiGHT MSH6 VCEP threshold for PM2_Supporting (allele frequency < 0.00002, i.e., <1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
PP3 ModerateThe HCI prior probability for pathogenicity is 0.9346, which exceeds the InSiGHT MSH6 VCEP threshold of >0.81 for PP3_Moderate in missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.9346 (>0.81 threshold for PP3_Moderate).
- REVEL score = 0.807 (supportive).
- SpliceAI max delta = 0.00 (no predicted splice impact).
Sources
hci_priorcspec ↗
Not met · 13 · evaluated, threshold not reached
PS1 No different nucleotide change encoding the same amino acid substitution (Gly599Glu) has been previously classified as Pathogenic or Likely Pathogenic by this VCEP. Details ▾Hide ▴
PS2 No de novo occurrence data are available for this variant. The InSiGHT MSH6 VCEP requires de novo points from confirmed parentage testing. Details ▾Hide ▴
Evidence considered
- No de novo observations reported.
Still missing
- No de novo case data available.
Sources
PS3 No variant-specific functional assay data or calibrated functional odds for pathogenicity are available for c.1796G>A (p.Gly599Glu). The variant was not listed in the VCEP MMR functional assay SVI documentation spreadsheet, and no independent functional studies were identified in the literature. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP MMR functional assay SVI documentation. No functional odds for pathogenicity available. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.
Still missing
- No functional assay data for this variant.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr
PM5 No different missense change at amino acid residue Gly599 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MSH6 VCEP. The PM5 candidate search identified zero comparator variants at this residue. Details ▾Hide ▴
Evidence considered
- No comparator missense variant at codon 599 classified as P/LP by this VCEP.
Sources
cspec ↗pm5_candidates
PP1 No co-segregation data with Bayes likelihood ratios are available for this variant. Details ▾Hide ▴
Evidence considered
- No pedigree or co-segregation data available.
Still missing
- No family segregation data.
Sources
PP4 No MSI-H tumor data or MMR protein immunohistochemistry results are available for this variant. The InSiGHT MSH6 VCEP requires MSI-H status or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor MSI/IHC data available.
Still missing
- No tumor phenotype data.
Sources
BA1 The variant is absent from all gnomAD population databases. The InSiGHT MSH6 VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%), which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency effectively zero.
Sources
BS1 The variant is absent from all gnomAD population databases. The InSiGHT MSH6 VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency effectively zero.
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available.
Still missing
- No co-occurrence or phase data.
Sources
BS3 No calibrated functional assay data with functional odds for pathogenicity ≤ 0.05 (BS3_Strong) or ≤ 0.48 (BS3_Supporting) are available for this variant. No variant-specific proficient function has been demonstrated in protein or mRNA-based laboratory assays per the MMR functional assay flowchart. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP MMR functional assay SVI documentation.
Still missing
- No functional assay data for this variant.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data are available to evaluate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No pedigree or segregation data available.
Still missing
- No family segregation data.
Sources
BP4 The HCI prior probability for pathogenicity is 0.9346, which substantially exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of < 0.11. In silico predictions are consistent with a deleterious effect, not a benign one. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.9346 (far above BP4 threshold of <0.11).
- REVEL = 0.807 (deleterious).
Sources
hci_priorcspec ↗
BP5 No tumor data (MSS status, MMR IHC, BRAF V600E mutation, MLH1 methylation) are available for this variant to support a benign interpretation. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available.
Still missing
- No tumor MSS/IHC/BRAF/MLH1 data.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. c.1796G>A (p.Gly599Glu) is a missense substitution and does not fall into any PVS1 null-variant category (nonsense, frameshift, canonical splice ±1,2, initiation codon) under the InSiGHT MSH6 VCEP v2.0. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 599
- variant class is not a null variant eligible for PVS1 per VCEP rules.
Sources
PS4 VCEPPS4 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
PM1 VCEPPM1 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
PM6 VCEPPM6 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
PP2 VCEPPP2 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
PP5 VCEPPP5 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. The ClinVar record (VariationID 2693765) has 1-star review status (criteria provided, single submitter), which does not trigger the PP5 global override threshold (requires 3-star expert panel). Details ▾Hide ▴
Evidence considered
- PP5 is not used by this VCEP. ClinVar classification is Uncertain significance with 1-star review status.
Sources
BP1 VCEPBP1 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
BP2 VCEPBP2 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- not an in-frame indel.
BP6 VCEPBP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond position -21/+7. c.1796G>A is a missense substitution and does not meet this criterion. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT MSH6 VCEP v2.0 criteria set. This VCEP does not use PS5. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.2
- Coding (HGVS c.)
- NM_000179.2:c.1796G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Gly599Glu)
- GRCh38
- chr2:47799779 G>A
- GRCh37
- chr2:48026918 G>A
- ClinVar
- 2693765, 89309
Gene diagram
Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.2. Select a row to find it on the plot.
MSH6NM_000179.2
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
0 / 0 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.807
- BayesDel
- 0.365
How the predictions were used
PP3 ModerateThe HCI prior probability for pathogenicity is 0.9346, which exceeds the InSiGHT MSH6 VCEP threshold of >0.81 for PP3_Moderate in missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.9346 (>0.81 threshold for PP3_Moderate).
- REVEL score = 0.807 (supportive).
- SpliceAI max delta = 0.00 (no predicted splice impact).
Sources
hci_priorcspec ↗
BP4 The HCI prior probability for pathogenicity is 0.9346, which substantially exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of < 0.11. In silico predictions are consistent with a deleterious effect, not a benign one. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.9346 (far above BP4 threshold of <0.11).
- REVEL = 0.807 (deleterious).
Sources
hci_priorcspec ↗
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond position -21/+7. c.1796G>A is a missense substitution and does not meet this criterion. Details ▾Hide ▴
Statement
In silico
In progress — evidence not uploaded yet.
1 paper record 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 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
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/2693765/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48026918-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47799779-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47799779-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.2%3Ac.1796…
- OncoKB ↗www.oncokb.org/gene/MSH6/G599E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.1796G%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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
In progress — evidence not uploaded yet.
In silico
In progress — evidence not uploaded yet.
Functional
In progress — evidence not uploaded yet.
Somatic
In progress — evidence not uploaded yet.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Literature
In progress — evidence not uploaded yet.