About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3334G>A, p.(Asp1112Asn)
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: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
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: none; 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
76 / 1,613,996 alleles
gnomAD v4.1: 76 / 1,613,996 alleles. Recorded AF 4.70881e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.82935e-05; MAF= 0.00283%, 8/282750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.1978e-05; MAF= 0.00620%, 8/129078 alleles, homozygotes = 0); grpmax FAF= 2.855e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
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
17 reported laboratory submissions
14 Uncertain significance · 2 Likely benign · 1 Uncertain Significance.
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.
28 criteria with recorded statuses: 0 met · 5 not met · 11 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 MSH6 NM_000179.3:c.3334G>A (p.Asp1112Asn, p.D1112N) variant has been reported in ClinVar with predominantly uncertain significance submissions and a smaller number of likely benign submissions.
This variant is present in population databases, including gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709; grpmax FAF 0.00004535) and gnomAD v2.1 at 8/282750 alleles (AF 0.00002829), and is absent from gnomAD-Canada; the gnomAD v4.1 frequency is above the MSH6 PM2 threshold of <0.00002 but below the BS1 threshold of 0.00022.
For MSH6 missense prediction, the HCI prior probability is 0.5901, which is below the PP3 thresholds of >0.68 and >0.81 and above the BP4 threshold of <0.11; REVEL is 0.71, BayesDel is -0.0786, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04.
No criteria match.
Not met · 5 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709), which is above the MSH6 PM2 threshold of <0.00002, so PM2 is not met. It is absent from gnomAD-Canada, but the gnomAD v4.1 frequency exceeds the VCEP rarity cutoff. Details ▾Hide ▴
Rule
Absent or extremely rare in gnomAD v4 at <0.00002
Evidence considered
- gnomAD v4.1 total AF 0.00004709 (76/1613996)
- gnomAD-Canada absent
- MSH6 PM2 threshold <0.00002
Sources
PP3 For MSH6 missense variants, PP3 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is below the PP3_Supporting threshold of >0.68 and below the PP3_Moderate threshold of >0.81, so PP3 is not met. REVEL is 0.71 and BayesDel is -0.0786, but the VCEP missense rule prioritizes the HCI prior for MSH6. SpliceAI predicts no significant splice effect with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability >0.68 for Supporting or >0.81 for Moderate
Evidence considered
- HCI prior probability 0.5901
- REVEL 0.71
- BayesDel -0.0786165
- SpliceAI max delta 0.04
Sources
BA1 The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BA1 threshold of 0.0022, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.0022
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00004535
- MSH6 BA1 threshold 0.0022
Sources
BS1 The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BS1 threshold of 0.00022, so BS1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.00022 and <0.0022
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00004535
- MSH6 BS1 threshold 0.00022
Sources
BP4 For MSH6 missense variants, BP4 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is above the BP4 threshold of <0.11, so BP4 is not met. SpliceAI shows a low maximum delta score of 0.04, but the missense-specific HCI prior rule does not support BP4 here. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability <0.11
Evidence considered
- HCI prior probability 0.5901
- BP4 threshold <0.11 for MSH6 missense
- SpliceAI max delta 0.04
Sources
Not assessed · 11 · no assessment recorded
PS1 No previously established pathogenic or likely pathogenic alternate nucleotide change producing the same amino acid substitution was identified, so PS1 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Same amino acid change previously established as Pathogenic or Likely Pathogenic under MSH6 VCEP rules
Evidence considered
- No qualifying PS1 comparator identified in the reviewed materials
Still missing
- Confirmed VCEP-established same amino acid comparator with a different nucleotide change
- RNA evidence if a comparator could be splice-driven
Sources
PS2 No confirmed de novo data were identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
De novo points under MSH6 VCEP PS2 rules
Evidence considered
- No de novo evidence identified
Still missing
- Parental testing and phenotype data for de novo point assignment
Sources
PS3 No variant-specific calibrated functional evidence showing an MMR defect or marked allelic expression loss was identified, so PS3 cannot be applied. Details ▾Hide ▴
Rule
Calibrated pathogenic functional evidence under MSH6 VCEP PS3 rules
Evidence considered
- No reviewed variant-specific functional evidence identified in the retrieved materials
Still missing
- Variant-specific calibrated protein functional assay results
- Variant-specific RNA or allelic expression assay results if available
Sources
PM3 No qualifying observations in trans with another pathogenic MSH6 variant in the constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
CMMRD point-based in trans evidence under MSH6 VCEP PM3 rules
Evidence considered
- No qualifying PM3 observations identified
Still missing
- Phase-confirmed in trans observations
- Phenotypic details for CMMRD point assignment
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PM5 No verified same-residue pathogenic or likely pathogenic missense comparator at codon 1112 was identified from the available comparator materials, so PM5 cannot be applied from the current evidence. In addition, the MSH6 VCEP requires missense PM5 to be used only when PP3 is met for the index variant, which is not the case here. Details ▾Hide ▴
Rule
Same-residue missense comparator under MSH6 VCEP PM5 rules with PP3 prerequisite
Evidence considered
- No qualifying same-residue comparator identified in available materials
- PP3 not met
Still missing
- Confirmed same-residue pathogenic or likely pathogenic missense comparator established under the governing framework
Sources
cspec ↗pm5_candidates
PP1 No segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
Rule
Co-segregation with disease using Bayes likelihood ratio thresholds
Evidence considered
- No segregation evidence identified
Still missing
- Pedigree data with Bayes likelihood ratio calculation
Sources
PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry results were identified to support the MSH6-specific PP4 tumor phenotype thresholds. Details ▾Hide ▴
Rule
MSI-H and/or loss of MMR protein expression meeting MSH6 VCEP thresholds
Evidence considered
- No qualifying MSI/IHC evidence identified
Still missing
- MSI testing results
- MMR immunohistochemistry results
- Number of independent qualifying tumors
Sources
BS2 No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusions was identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Confirmed in trans co-occurrence with a known pathogenic variant under MSH6 VCEP BS2 rules
Evidence considered
- No qualifying co-occurrence evidence identified in the reviewed materials
Still missing
- Phase-confirmed co-occurrence data
- Clinical details needed to exclude CMMRD and confirm age criteria
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No variant-specific calibrated functional evidence showing proficient MMR function or normal RNA effect was identified, so BS3 cannot be applied. Details ▾Hide ▴
Rule
Calibrated benign functional evidence or normal RNA evidence under MSH6 VCEP BS3 rules
Evidence considered
- No reviewed variant-specific functional evidence identified in the retrieved materials
Still missing
- Variant-specific protein functional assay results
- Variant-specific RNA assay results if available
Sources
BS4 No non-segregation data were identified, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Lack of co-segregation using Bayes likelihood ratio thresholds
Evidence considered
- No non-segregation evidence identified
Still missing
- Pedigree data with Bayes likelihood ratio calculation for lack of segregation
Sources
BP5 No tumor findings showing MSS, retained MMR protein expression, or inconsistent MMR loss patterns were identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
Benign tumor phenotype evidence under MSH6 VCEP BP5 rules
Evidence considered
- No qualifying tumor phenotype evidence identified
Still missing
- Tumor MSI results
- Tumor IHC results
- BRAF/MLH1 methylation results where relevant
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a truncating or canonical splice variant, and the variant-specific PVS1 assessment states that it does not fall into a default null-variant bucket. PVS1 is therefore not applicable. Details ▾Hide ▴
Rule
PVS1 applies to qualifying loss-of-function variant classes under MSH6 VCEP rules
Evidence considered
- Protein consequence p.(Asp1112Asn)
- Variant bucket other
- Generic PVS1 scaffold not applicable
Sources
PS4 VCEPPS4 is not used by this VCEP. Details ▾Hide ▴
PM1 VCEPPM1 is not used by this VCEP. Details ▾Hide ▴
PM4 VCEPPM4 is not used by this VCEP. Details ▾Hide ▴
PM6 VCEPPM6 is not used by this VCEP. Details ▾Hide ▴
PP2 VCEPPP2 is not used by this VCEP. Details ▾Hide ▴
PP5 VCEPPP5 is not used by this VCEP. Details ▾Hide ▴
BP1 VCEPBP1 is not used by this VCEP. Details ▾Hide ▴
BP2 VCEPBP2 is not used by this VCEP. Details ▾Hide ▴
BP3 VCEPBP3 is not used by this VCEP. Details ▾Hide ▴
BP6 VCEPBP6 is not used by this VCEP. Details ▾Hide ▴
BP7 N/AThis is a missense variant, not a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant with no predicted splice impact
Evidence considered
- Protein consequence p.(Asp1112Asn)
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3334G>A
- Protein (HGVS p.)
- NP_000170.1:p.(Asp1112Asn)
- GRCh38
- chr2:47803581 G>A
- GRCh37
- chr2:48030720 G>A
- ClinVar
- 220784
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
76 / 1,613,996 alleles
AF 4.71e-05 · 0 homozygotes · FAF 4.53e-05
gnomAD v2.1
8 / 282,750 alleles
AF 2.83e-05 · 0 homozygotes · FAF 2.86e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.7e-05 · 76 / 1,613,996 alleles · 0 hom · FAF 4.5e-05
| Remaining individuals8 / 62,488 | 0.00013 |
| European (non-Finnish)67 / 1,180,032 | 5.7e-05 |
| African/African American1 / 74,902 | 1.3e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 2.8e-05 · 8 / 282,750 alleles · 0 hom · FAF 2.9e-05
| European (non-Finnish)8 / 129,078 | 6.2e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.70881e-05; MAF= 0.00471%, 76/1613996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000128025; MAF= 0.01280%, 8/62488 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.82935e-05; MAF= 0.00283%, 8/282750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.1978e-05; MAF= 0.00620%, 8/129078 alleles, homozygotes = 0); grpmax FAF= 2.855e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.710
- BayesDel
- -0.079
How the predictions were used
PP3 For MSH6 missense variants, PP3 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is below the PP3_Supporting threshold of >0.68 and below the PP3_Moderate threshold of >0.81, so PP3 is not met. REVEL is 0.71 and BayesDel is -0.0786, but the VCEP missense rule prioritizes the HCI prior for MSH6. SpliceAI predicts no significant splice effect with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability >0.68 for Supporting or >0.81 for Moderate
Evidence considered
- HCI prior probability 0.5901
- REVEL 0.71
- BayesDel -0.0786165
- SpliceAI max delta 0.04
Sources
BP4 For MSH6 missense variants, BP4 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is above the BP4 threshold of <0.11, so BP4 is not met. SpliceAI shows a low maximum delta score of 0.04, but the missense-specific HCI prior rule does not support BP4 here. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability <0.11
Evidence considered
- HCI prior probability 0.5901
- BP4 threshold <0.11 for MSH6 missense
- SpliceAI max delta 0.04
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant with no predicted splice impact
Evidence considered
- Protein consequence p.(Asp1112Asn)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.71. BayesDel score = -0.0786165. HCI prior probability for pathogenicity = 0.5901. MAPP score = 13.97. Custom PP2 score = 0.84.
11 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 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 26689913 ↗Patterns and functional implications of rare germline variants across 12 cancer types.Lu C et al. · 2015No paper-specific finding is recorded.
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.No paper-specific finding is recorded.
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.No paper-specific finding is recorded.
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PMID 20301390 ↗PMID:20301390No paper-specific finding is recorded.
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PMID 20301425 ↗PMID:20301425No paper-specific finding is recorded.
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PMID 24905773 ↗Endometrial cancer: a review and current management strategies: part I.SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014No paper-specific finding is recorded.
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PMID 24929052 ↗Endometrial cancer: a review and current management strategies: part II.SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014No 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.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
76 / 1,613,996 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
14 Uncertain significance · 2 Likely benign · 1 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/220784/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48030720-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47803581-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47803581-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3334…
- OncoKB ↗www.oncokb.org/gene/MSH6/D1112N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.3334G%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
This variant is present in gnomAD v4.1 (AF= 4.70881e-05; MAF= 0.00471%, 76/1613996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000128025; MAF= 0.01280%, 8/62488 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.82935e-05; MAF= 0.00283%, 8/282750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.1978e-05; MAF= 0.00620%, 8/129078 alleles, homozygotes = 0); grpmax FAF= 2.855e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (14 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 220784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.71. BayesDel score = -0.0786165. HCI prior probability for pathogenicity = 0.5901. MAPP score = 13.97. Custom PP2 score = 0.84.
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.