About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.-2G>T, p.?
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
This variant is present at very low frequency in gnomAD v4.1 with a total allele frequency of 1.24133e-05 (20/1611176 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002, so PM2_Supporting is met.
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
20 / 1,611,176 alleles
gnomAD v4.1: 20 / 1,611,176 alleles. Recorded AF 1.24133e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
13 reported laboratory submissions
8 Uncertain significance · 5 Likely benign.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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: 1 met · 3 not met · 9 not assessed · 15 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.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.
This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 1.24133e-05 (20/1611176 alleles) and gnomAD v2.1 total allele frequency 1.45244e-05 (4/275398 alleles), which supports PM2_Supporting under the MSH6 VCEP threshold of less than 0.00002.
Available evidence does not show a qualifying constitutional RNA or other calibrated functional study for this variant, so PS3 and BS3 are not currently supported.
SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.00, but this 5′ UTR substitution does not fit the MSH6 VCEP PP3 or BP4 rule types for missense or qualifying intronic/non-canonical splice variants.
No criteria match.
Met · 1
PM2 SupportingThis variant is present at very low frequency in gnomAD v4.1 with a total allele frequency of 1.24133e-05 (20/1611176 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002, so PM2_Supporting is met. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 total AF 1.24133e-05
- gnomAD v2.1 total AF 1.45244e-05
- MSH6 VCEP PM2 threshold <0.00002
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 Although the generic scaffold flagged canonical splice review, this variant is annotated as NM_000179.3:c.-2G>T, a 5′ UTR substitution immediately upstream of the coding start. It does not alter the initiation codon and does not meet the MSH6 VCEP null-variant categories for nonsense, frameshift, canonical ±1/2 splice, or qualifying RNA-proven splice defects, so PVS1 is not applied. Details ▾Hide ▴
Rule
Null variant in a gene where loss of function is a known mechanism of disease, with MSH6-specific splice/truncation rules.
Evidence considered
- Variant HGVS NM_000179.3:c.-2G>T
- MSH6 VCEP PVS1 rule reviewed
- Generic scaffold reviewed and overruled by transcript-coordinate context
Still missing
- If independent evidence demonstrates a true constitutional splice defect from this 5′ UTR variant
- RNA review would be needed.
Sources
BA1 The gnomAD v4.1 filtering allele frequency is 2.987e-05, which is below the MSH6 VCEP BA1 threshold of 0.0022, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.987e-05
- MSH6 VCEP BA1 threshold 0.0022
Sources
BS1 The gnomAD v4.1 filtering allele frequency is 2.987e-05, which is below the MSH6 VCEP 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 2.987e-05
- MSH6 VCEP BS1 threshold 0.00022
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data were identified, so PS2 was not assessed. Details ▾Hide ▴
Rule
De novo points system with strength based on total points.
Evidence considered
- MSH6 VCEP PS2 rule reviewed
- No de novo evidence identified
Still missing
- Confirmed maternity and paternity with qualifying tumor phenotype were not available.
Sources
PS3 No variant-specific calibrated functional assay or constitutional RNA study demonstrating an abnormal effect was identified, so PS3 was not assessed. Details ▾Hide ▴
Rule
Calibrated functional assays above pathogenic odds thresholds, MMR function defect following functional assay flowchart, or qualifying monoallelic expression loss.
Evidence considered
- MSH6 VCEP PS3 rule reviewed
- No qualifying pathogenic functional evidence identified
Still missing
- A qualifying damaging functional or RNA assay result was not available.
Sources
PM3 No qualifying in trans observations for constitutional mismatch repair deficiency scoring were identified, so PM3 was not assessed. Details ▾Hide ▴
Rule
Points-based in trans evidence framework for recessive/CMMRD presentations.
Evidence considered
- MSH6 VCEP PM3 rule reviewed
- No qualifying in trans evidence identified
Still missing
- Case-level biallelic/in trans evidence was not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified to calculate the Bayes likelihood ratio required for PP1, so this criterion was not assessed. Details ▾Hide ▴
Rule
Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio above the VCEP thresholds.
Evidence considered
- MSH6 VCEP PP1 rule reviewed
- No pedigree-based segregation evidence identified
Still missing
- Family segregation data were not available.
Sources
PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
Tumor MSI-H and/or loss of MMR protein expression consistent with the variant location, with strength based on the number of independent tumors/families.
Evidence considered
- MSH6 VCEP PP4 rule reviewed
- No qualifying tumor phenotype evidence identified
Still missing
- MSI and/or IHC results consistent with MSH6-associated mismatch repair deficiency were not available.
Sources
BS2 No confirmed in trans observation with a pathogenic MSH6 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS), and who has no previous or current evidence of clinical manifestations of CMMRD.
Evidence considered
- MSH6 VCEP BS2 rule reviewed
- No qualifying case-level co-occurrence evidence identified
Still missing
- Documented phase-confirmed in trans observations with relevant clinical phenotype were not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No variant-specific RNA or other calibrated functional assay showing no damaging effect was identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05, or qualifying constitutional RNA studies showing no associated mRNA aberration.
Evidence considered
- MSH6 VCEP BS3 rule reviewed
- No qualifying benign functional evidence identified
Still missing
- A qualifying negative functional or constitutional RNA assay result was not available.
Sources
BS4 No segregation data showing lack of co-segregation with disease were identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio below the VCEP thresholds.
Evidence considered
- MSH6 VCEP BS4 rule reviewed
- No non-segregation evidence identified
Still missing
- Family data sufficient to calculate a Bayes likelihood ratio for non-segregation were not available.
Sources
BP5 No qualifying evidence for an alternate molecular explanation with mismatch repair findings inconsistent with MSH6 was identified, so BP5 was not assessed. Details ▾Hide ▴
Rule
Tumors with MSS and/or no loss of MMR protein expression or inconsistent protein loss, or qualifying MLH1 methylation/BRAF evidence.
Evidence considered
- MSH6 VCEP BP5 rule reviewed
- No qualifying alternate molecular basis evidence identified
Still missing
- Tumor and alternate-cause data required by the VCEP BP5 rule were not available.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is neither a missense substitution nor a non-canonical splice nucleotide with a previously established pathogenic comparator, so PS1 is not applicable. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic missense variant, or same non-canonical splice nucleotide as a pathogenic splice variant with similar or worse SpliceAI prediction.
Evidence considered
- Variant HGVS NM_000179.3:c.-2G>T
- MSH6 VCEP PS1 rule reviewed
Sources
PS4 VCEPPS4 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
PM1 VCEPPM1 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
PM4 VCEPPM4 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
PM5 N/AThe MSH6 PM5 rule uses classic same-residue missense logic, and this variant is not missense-like, so PM5 is not applicable. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different missense change was previously established as pathogenic or likely pathogenic on the protein level.
Evidence considered
- PM5 candidate review found classic same-residue missense mode only
- Variant is not missense-like
Sources
pm5_candidatescspec ↗
PM6 VCEPPM6 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
PP2 VCEPPP2 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
PP3 N/AThe MSH6 VCEP PP3 rule is specified for missense variants using HCI priors or for predicted splice defects at non-canonical splice nucleotides with SpliceAI delta score at least 0.2. This c.-2 5′ UTR substitution is not missense, is not a non-canonical splice nucleotide, and SpliceAI shows a max delta score of 0.00, so PP3 is not applied. Details ▾Hide ▴
Rule
Missense variant with HCI prior >0.68, or predicted splice defect for non-canonical splicing nucleotides using SpliceAI delta score ≥0.2.
Evidence considered
- SpliceAI max delta score 0.00
- No HCI prior because variant is not missense
- MSH6 VCEP PP3 rule reviewed
Sources
PP5 VCEPPP5 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
BP1 VCEPBP1 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
BP2 VCEPBP2 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
BP3 VCEPBP3 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact with a max delta score of 0.00, but the MSH6 VCEP BP4 rule is specified for missense variants using HCI priors or for intronic and synonymous variants, and this c.-2 5′ UTR substitution does not fit those rule types, so BP4 is not applied. Details ▾Hide ▴
Rule
Missense variant with HCI-prior probability of pathogenicity <0.11, or for intronic and synonymous variants SpliceAI delta score ≤0.1.
Evidence considered
- SpliceAI max delta score 0.00
- No HCI prior because variant is not missense
- MSH6 VCEP BP4 rule reviewed
Sources
BP6 VCEPBP6 is not used by this MSH6 VCEP specification. Details ▾Hide ▴
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- MSH6 VCEP marks BP6 not applicable
Sources
BP7 N/AThis is a 5′ UTR substitution at c.-2 rather than a synonymous change or an intronic variant at or beyond the BP7 distance rule, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Variant HGVS NM_000179.3:c.-2G>T
- MSH6 VCEP BP7 rule reviewed
Sources
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.-2G>T
- Protein (HGVS p.)
- NP_000170.1:p.?
- GRCh38
- chr2:47783232 G>T
- GRCh37
- chr2:48010371 G>T
- ClinVar
- 231964, 142219
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
20 / 1,611,176 alleles
AF 1.24e-05 · 0 homozygotes · FAF 2.99e-05
gnomAD v2.1
4 / 275,398 alleles
AF 1.45e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 20 / 1,611,176 alleles · 0 hom · FAF 3e-05
| Remaining individuals15 / 62,396 | 0.00024 |
| East Asian4 / 44,672 | 9e-05 |
| European (non-Finnish)1 / 1,179,344 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.5e-05 · 4 / 275,398 alleles · 0 hom
| Remaining individuals1 / 7,088 | 0.00014 |
| East Asian2 / 19,398 | 0.0001 |
| South Asian1 / 30,236 | 3.3e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24133e-05; MAF= 0.00124%, 20/1611176 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.0002404; MAF= 0.02404%, 15/62396 alleles, homozygotes = 0); grpmax FAF= 2.987e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AThe MSH6 VCEP PP3 rule is specified for missense variants using HCI priors or for predicted splice defects at non-canonical splice nucleotides with SpliceAI delta score at least 0.2. This c.-2 5′ UTR substitution is not missense, is not a non-canonical splice nucleotide, and SpliceAI shows a max delta score of 0.00, so PP3 is not applied. Details ▾Hide ▴
Rule
Missense variant with HCI prior >0.68, or predicted splice defect for non-canonical splicing nucleotides using SpliceAI delta score ≥0.2.
Evidence considered
- SpliceAI max delta score 0.00
- No HCI prior because variant is not missense
- MSH6 VCEP PP3 rule reviewed
Sources
BP4 N/ASpliceAI predicts no significant splice impact with a max delta score of 0.00, but the MSH6 VCEP BP4 rule is specified for missense variants using HCI priors or for intronic and synonymous variants, and this c.-2 5′ UTR substitution does not fit those rule types, so BP4 is not applied. Details ▾Hide ▴
Rule
Missense variant with HCI-prior probability of pathogenicity <0.11, or for intronic and synonymous variants SpliceAI delta score ≤0.1.
Evidence considered
- SpliceAI max delta score 0.00
- No HCI prior because variant is not missense
- MSH6 VCEP BP4 rule reviewed
Sources
BP7 N/AThis is a 5′ UTR substitution at c.-2 rather than a synonymous change or an intronic variant at or beyond the BP7 distance rule, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic).
Evidence considered
- Variant HGVS NM_000179.3:c.-2G>T
- MSH6 VCEP BP7 rule reviewed
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 25070057 ↗Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.Giardiello FM et al. · 2014No paper-specific finding is recorded.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.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 26888055 ↗Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.Liu Q et al. · 2016No paper-specific finding is recorded.
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PMID 28301460 ↗Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.Harrison SM et al. · 2017No paper-specific finding is recorded.
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PMID 33939675 ↗Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing.Zhu H et al. · 2021No paper-specific finding is recorded.
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PMID 34197922 ↗Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition.Lau TTY 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.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
20 / 1,611,176 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
8 Uncertain significance · 5 Likely benign
Open source ↗
COSMIC
Captured COSMIC 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/142219/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48010371-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47783232-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.-2G%…
- OncoKB ↗www.oncokb.org/gene/MSH6/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.-2G%3ET
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= 1.24133e-05; MAF= 0.00124%, 20/1611176 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.0002404; MAF= 0.02404%, 15/62396 alleles, homozygotes = 0); grpmax FAF= 2.987e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 142219)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).