About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.3483T>C, p.(Pro1161=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.86e-06 (3/1,614,056 alleles), which is below the MSH6 PM2_Supporting threshold of 0.00002.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
Computational splice prediction supports a benign interpretation. For this synonymous variant, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 BP4 threshold of 0.1 for no predicted splicing impact.
BP7Supporting
BP7 · supporting
This is a synonymous MSH6 variant, NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)), located well away from the splice junctions in exon 6 (44 nucleotides from the acceptor and 73 nucleotides from the donor), which satisfies the BP7 location requirement for a silent exonic change beyond -21/+7.
Recorded classification: Likely benign
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 Rule19 (Benign.Supporting >=2) with applied criteria: BP7 supporting, PM2 supporting, BP4 supporting; maps to Likely Benign.
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
3 / 1,614,056 alleles
gnomAD v4.1: 3 / 1,614,056 alleles. Recorded AF 1.85867e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95551e-06; MAF= 0.00080%, 2/251398 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108743; MAF= 0.01087%, 2/18392 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
4 Likely benign · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 3 met · 4 not met · 9 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.3483T>C (NP_000170.1:p.(Pro1161=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 4 likely benign and 1 benign clinical laboratory submissions.
This variant is rare in population databases, with gnomAD v4.1 overall AF 1.86e-06 (3/1,614,056 alleles) and highest observed subpopulation AF 3.20e-05 (2/62,482 alleles), which is below the MSH6 BS1 threshold of 0.00022 and BA1 threshold of 0.0022 but within the PM2_Supporting rarity threshold of <0.00002.
This is a synonymous change, NP_000170.1:p.(Pro1161=), located 44 nucleotides from the exon 6 acceptor and 73 nucleotides from the donor, and SpliceAI predicts no splice effect (max delta score 0.00), supporting BP7 and BP4 rather than PP3.
No criteria match.
Met · 3
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.86e-06 (3/1,614,056 alleles), which is below the MSH6 PM2_Supporting threshold of 0.00002. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 in gnomAD v4.
Evidence considered
- gnomAD v4.1 overall AF 1.85867e-06 (3/1614056)
- MSH6 PM2 threshold <0.00002
Sources
BP4 SupportingComputational splice prediction supports a benign interpretation. For this synonymous variant, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 BP4 threshold of 0.1 for no predicted splicing impact. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <=0.1.
Evidence considered
- SpliceAI max delta score 0.00
- MSH6 BP4 threshold <=0.1 for synonymous/intronic variants
Sources
BP7 SupportingThis is a synonymous MSH6 variant, NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)), located well away from the splice junctions in exon 6 (44 nucleotides from the acceptor and 73 nucleotides from the donor), which satisfies the BP7 location requirement for a silent exonic change beyond -21/+7. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Synonymous protein consequence p.(Pro1161=)
- Exon 6 position is beyond the BP7 splice-region exclusion zone
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 PVS1 is not met. This variant is a synonymous change, NP_000170.1:p.(Pro1161=), and does not fall into the MSH6 null-variant categories used for PVS1. No RNA evidence was identified showing a splice aberration that would create a loss-of-function effect. Details ▾Hide ▴
Rule
MSH6 PVS1 applies to qualifying loss-of-function or confirmed splice-defect scenarios.
Evidence considered
- Variant is synonymous rather than nonsense
- frameshift
- or canonical splice
- Generic PVS1 scaffold indicates this variant is outside default PVS1 buckets
Sources
PP3 Computational evidence does not support PP3. For non-canonical splice prediction, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 PP3 threshold of 0.2. The HCI prior rule applies to missense variants and is not relevant to this synonymous change. Details ▾Hide ▴
Rule
For non-canonical splice prediction, SpliceAI delta score >=0.2; missense uses HCI prior thresholds.
Evidence considered
- SpliceAI max delta score 0.00
- PP3 splice threshold >=0.2
- Variant is synonymous
- not missense
Sources
BA1 Population data do not meet BA1. In gnomAD v4.1, the highest observed subpopulation allele frequency is 0.00320% (2/62,482 alleles), which is below the MSH6 BA1 threshold of 0.22%. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.0022 (0.22%).
Evidence considered
- gnomAD v4.1 highest observed subpopulation AF 3.20092e-05
- MSH6 BA1 threshold >=0.0022
Sources
BS1 Population data do not meet BS1. In gnomAD v4.1, the highest observed subpopulation allele frequency is 0.00320% (2/62,482 alleles), which is below the MSH6 BS1 range of 0.022% to 0.22%. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.00022 and <0.0022.
Evidence considered
- gnomAD v4.1 highest observed subpopulation AF 3.20092e-05
- MSH6 BS1 threshold >=0.00022 and <0.0022
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo data were identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
De novo points meeting VCEP thresholds.
Evidence considered
- No de novo evidence identified
Still missing
- Confirmed maternity and paternity
- De novo scoring information
Sources
PS3 No calibrated pathogenic functional assay or variant-specific RNA evidence demonstrating an abnormal effect was identified, so PS3 cannot be assessed. Details ▾Hide ▴
Rule
Qualifying calibrated pathogenic functional assay or other VCEP-approved abnormal functional evidence.
Evidence considered
- No qualifying PS3 evidence identified
Still missing
- Variant-specific functional assay data
- Variant-specific constitutional RNA studies showing abnormal effect
Sources
PM3 No qualifying recessive phase data or point-based in trans observations were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Point-based in trans observations meeting VCEP thresholds.
Evidence considered
- No qualifying PM3 evidence identified
Still missing
- Confirmed in trans observations
- PM3 point-based case data
Sources
PP1 No segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
Co-segregation with disease with Bayes LR above VCEP thresholds.
Evidence considered
- No segregation evidence identified
Still missing
- Pedigree-based segregation data
- Bayes likelihood ratio calculation
Sources
PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified, so PP4 cannot be assessed. Details ▾Hide ▴
Rule
Tumor MSI-H and/or MMR protein loss evidence meeting MSH6 VCEP thresholds.
Evidence considered
- No qualifying tumor phenotype data identified
Still missing
- MSI testing results
- MMR IHC results
- Number of independent qualifying tumors/families
Sources
BS2 No phase-confirmed in trans observation with a known pathogenic MSH6 variant in an older patient without clinical features of CMMRD was identified, so BS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
In trans co-occurrence with a known pathogenic MSH6 variant in an appropriate clinical context.
Evidence considered
- No qualifying co-occurrence evidence identified
Still missing
- Case-level co-occurrence and phase data
- Clinical assessment for CMMRD features
Sources
BS3 No RNA study with nonsense-mediated decay inhibition or other qualifying calibrated benign functional assay was identified for this variant, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
For synonymous/intronic variants, no associated mRNA aberration on laboratory assays with NMD inhibition, or qualifying calibrated benign functional assay.
Evidence considered
- No qualifying BS3 assay evidence identified
Still missing
- Variant-specific constitutional RNA study
- Qualifying benign functional assay data
Sources
BS4 No non-segregation data were identified, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
Lack of co-segregation with Bayes LR below VCEP thresholds.
Evidence considered
- No BS4 segregation evidence identified
Still missing
- Pedigree-based non-segregation data
- Bayes likelihood ratio calculation
Sources
BP5 No tumor data showing mismatch repair findings inconsistent with MSH6-related disease were identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
Tumor findings inconsistent with the gene demonstrating variation, or qualifying BRAF/MLH1 methylation evidence.
Evidence considered
- No qualifying BP5 tumor evidence identified
Still missing
- Tumor MSS/MMR IHC data
- BRAF V600E or MLH1 methylation data where relevant
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThe MSH6 PS1 rule applies to missense substitutions causing the same amino acid change or to variants affecting the same non-canonical splice nucleotide as a known pathogenic or likely pathogenic splice variant. This synonymous exonic change does not fit those PS1 use cases. Details ▾Hide ▴
Rule
Missense same-amino-acid change or same non-canonical splice nucleotide comparator.
Evidence considered
- Variant consequence is synonymous p.(Pro1161=)
Sources
PS4 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PS4 as not applicable
Sources
PM1 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM1 as not applicable
Sources
PM4 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM4 as not applicable
Sources
PM5 N/APM5 is not applicable because the MSH6 PM5 rule is restricted to classic same-residue missense comparisons, and this variant is synonymous rather than missense. Details ▾Hide ▴
Rule
Classic same-residue missense comparator rule.
Evidence considered
- PM5 candidate review marked variant as not eligible for classic same-residue missense PM5
Sources
cspec ↗pm5_candidates
PM6 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PM6 as not applicable
Sources
PP2 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PP2 as not applicable
Sources
PP5 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks PP5 as not applicable
Sources
BP1 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP1 as not applicable
Sources
BP2 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP2 as not applicable
Sources
BP3 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP3 as not applicable
Sources
BP6 VCEPThis criterion is not used in the MSH6 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- MSH6 VCEP marks BP6 as not applicable
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.3483T>C
- Protein (HGVS p.)
- NP_000170.1:p.(Pro1161=)
- GRCh38
- chr2:47804954 T>C
- GRCh37
- chr2:48032093 T>C
- ClinVar
- 3903745, 380626
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
3 / 1,614,056 alleles
AF 1.86e-06 · 0 homozygotes
gnomAD v2.1
2 / 251,398 alleles
AF 7.96e-06 · 0 homozygotes · FAF 1.9e-05
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,056 alleles · 0 hom
| Remaining individuals2 / 62,482 | 3.2e-05 |
| East Asian1 / 44,900 | 2.2e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 8e-06 · 2 / 251,398 alleles · 0 hom · FAF 1.9e-05
| East Asian2 / 18,392 | 0.00011 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85867e-06; MAF= 0.00019%, 3/1614056 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95551e-06; MAF= 0.00080%, 2/251398 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108743; MAF= 0.01087%, 2/18392 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational splice prediction supports a benign interpretation. For this synonymous variant, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 BP4 threshold of 0.1 for no predicted splicing impact. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <=0.1.
Evidence considered
- SpliceAI max delta score 0.00
- MSH6 BP4 threshold <=0.1 for synonymous/intronic variants
Sources
BP7 SupportingThis is a synonymous MSH6 variant, NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)), located well away from the splice junctions in exon 6 (44 nucleotides from the acceptor and 73 nucleotides from the donor), which satisfies the BP7 location requirement for a silent exonic change beyond -21/+7. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Synonymous protein consequence p.(Pro1161=)
- Exon 6 position is beyond the BP7 splice-region exclusion zone
Sources
PP3 Computational evidence does not support PP3. For non-canonical splice prediction, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 PP3 threshold of 0.2. The HCI prior rule applies to missense variants and is not relevant to this synonymous change. Details ▾Hide ▴
Rule
For non-canonical splice prediction, SpliceAI delta score >=0.2; missense uses HCI prior thresholds.
Evidence considered
- SpliceAI max delta score 0.00
- PP3 splice threshold >=0.2
- Variant is synonymous
- not missense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 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 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
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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.
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PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.Kalia SS et al. · 2017No paper-specific finding is recorded.
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PMID 34012068 ↗ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).Miller DT et al. · 2021No paper-specific finding is recorded.
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PMID 34043773 ↗European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.Seppälä TT et al. · 2021No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,614,056 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
4 Likely benign · 1 Benign
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/380626/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48032093-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47804954-T-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.3483…
- OncoKB ↗www.oncokb.org/gene/MSH6/P1161=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.3483T%3EC
- 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= 1.85867e-06; MAF= 0.00019%, 3/1614056 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95551e-06; MAF= 0.00080%, 2/251398 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108743; MAF= 0.01087%, 2/18392 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 380626)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.