About MSH6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH6 c.260+21T>G, p.?
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
NM_000179.3:c.260+21T>G has an allele frequency of 4.32e-06 (6/1,388,350 alleles, grpmax FAF = 1.10e-05) in gnomAD v4.1, which is below the InSiGHT MSH6 VCEP v2.0.0 PM2_Supporting threshold of <0.00002 (1 in 50,000 alleles).
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
Under the InSiGHT MSH6 VCEP v2.0.0, BP4_Supporting is met for intronic variants when SpliceAI predicts no splicing impact with delta score ≤ 0.1. SpliceAI predicts no significant splice impact for NM_000179.3:c.260+21T>G (max delta score = 0.00).
BP7Supporting
BP7 · supporting
Under the InSiGHT MSH6 VCEP v2.0.0, BP7_Supporting applies to intronic variants at or beyond -21/+7 from the exon boundary. NM_000179.3:c.260+21T>G is located at position +21 in intron 1, which is beyond the +7 threshold, satisfying the VCEP BP7 rule.
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: PM2 supporting, BP4 supporting benign, BP7 supporting benign; 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
6 / 1,388,350 alleles
gnomAD v4.1: 6 / 1,388,350 alleles. Recorded AF 4.32168e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/34192 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/852 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.
ClinVar submissions
1 reported laboratory submissions
1 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.
27 criteria with recorded statuses: 3 met · 3 not met · 8 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.260+21T>G in MSH6 is an intronic variant located at position +21 of intron 1. SpliceAI predicts no splicing impact (max delta score = 0.00).
The variant is present at extremely low frequency in gnomAD v4.1 (6/1,388,350 alleles, AF = 4.32e-06, grpmax FAF = 1.10e-05), meeting the InSiGHT MSH6 VCEP v2.0.0 PM2_Supporting criterion (AF < 0.00002).
The variant is absent from gnomAD v2.1 (0/34,192 alleles).
SpliceAI predicts no splicing impact (max delta = 0.00), meeting the VCEP BP4_Supporting criterion (delta ≤ 0.1 for intronic variants).
The variant is intronic at position +21, meeting the VCEP BP7_Supporting criterion (intronic variant at or beyond +7 from the exon boundary).
The gnomAD v4.1 grpmax FAF (1.10e-05) does not meet VCEP BA1 (≥0.0022) or BS1 (≥0.00022) frequency thresholds.
This variant has been reported in ClinVar as Likely benign by one clinical laboratory (ClinVar Variation ID: 491905).
No criteria match.
Met · 3
PM2 SupportingNM_000179.3:c.260+21T>G has an allele frequency of 4.32e-06 (6/1,388,350 alleles, grpmax FAF = 1.10e-05) in gnomAD v4.1, which is below the InSiGHT MSH6 VCEP v2.0.0 PM2_Supporting threshold of <0.00002 (1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AC=6
- AN=1
- 388
- 350
- AF=4.32e-06
- grpmax FAF=1.10e-05
- all below the VCEP PM2_Supporting cutoff of 0.00002.
Sources
BP4 SupportingUnder the InSiGHT MSH6 VCEP v2.0.0, BP4_Supporting is met for intronic variants when SpliceAI predicts no splicing impact with delta score ≤ 0.1. SpliceAI predicts no significant splice impact for NM_000179.3:c.260+21T>G (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- meeting the VCEP BP4_Supporting threshold of ≤ 0.1 for intronic variants.
Sources
BP7 SupportingUnder the InSiGHT MSH6 VCEP v2.0.0, BP7_Supporting applies to intronic variants at or beyond -21/+7 from the exon boundary. NM_000179.3:c.260+21T>G is located at position +21 in intron 1, which is beyond the +7 threshold, satisfying the VCEP BP7 rule. Details ▾Hide ▴
Evidence considered
- Variant is intronic at position +21
- beyond the VCEP BP7 threshold of +7 from the exon boundary.
Sources
Not met · 3 · evaluated, threshold not reached
PP3 Under the InSiGHT MSH6 VCEP v2.0.0, PP3 applies to (a) missense variants with HCI prior >0.68, or (b) intronic/splice variants with SpliceAI delta score ≥ 0.2. This is an intronic variant and SpliceAI predicts no splicing impact (max delta score = 0.00), falling below the 0.2 threshold. The variant is not missense and has no HCI prior score. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (below PP3 threshold of 0.2)
- HCI prior not applicable (intronic variant not in missense lookup table).
Sources
BA1 Under the InSiGHT MSH6 VCEP v2.0.0, BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%). The grpmax FAF for this variant is 1.10e-05 (0.0011%), far below the BA1 stand-alone threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 1.10e-05 (0.0011%)
- VCEP BA1 threshold = 0.0022 (0.22%).
Sources
BS1 Under the InSiGHT MSH6 VCEP v2.0.0, BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022. The grpmax FAF for this variant is 1.10e-05 (0.0011%), below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 1.10e-05 (0.0011%)
- VCEP BS1 threshold = 0.00022 (0.022%).
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observation data are available for NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires de novo points (≥0.5) based on confirmed de novo occurrences; none have been identified in the evidence sources for this case. Details ▾Hide ▴
Still missing
- No de novo case data available for this variant.
PS3 No calibrated functional assay data are available for NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires functional odds for pathogenicity from calibrated assays or MMR functional defect data per the functional assay flowchart. The variant was not found in the VCEP functional assay documentation spreadsheet, and no functional evidence was identified in the literature or OncoKB. Details ▾Hide ▴
Still missing
- No functional assay data or mRNA splicing assay data available for this variant.
PP1 No co-segregation data are available for NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires Bayes likelihood ratios from pedigree analysis (≥2.08 for supporting, ≥4.3 for moderate, ≥18.7 for strong). No pedigree or segregation studies were identified in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
- No co-segregation or pedigree data available.
PP4 No tumor phenotype data (MSI status, MMR IHC) are available for carriers of NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Still missing
- No tumor MSI or IHC data available for variant carriers.
BS2 No data are available demonstrating co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. The InSiGHT MSH6 VCEP v2.0.0 requires confirmed phase and exclusion of CMMRD per the CMMRD diagnostic table. Details ▾Hide ▴
Still missing
- No co-occurrence in trans data available.
BS3 No calibrated functional assay data are available for NM_000179.3:c.260+21T>G. While SpliceAI predicts no splicing impact (delta = 0.00), the InSiGHT MSH6 VCEP v2.0.0 BS3 rule for intronic variants requires laboratory mRNA assays (with NMD inhibition) demonstrating no associated mRNA aberration. In silico prediction alone is insufficient to meet BS3. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splicing impact (max delta = 0.00)
- but VCEP BS3 requires laboratory mRNA functional assay data
- which are not available.
Still missing
- No mRNA splicing assay data from patient samples with NMD inhibition.
Sources
BS4 No co-segregation data are available for NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires Bayes likelihood ratios from pedigree analysis demonstrating lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No pedigree or segregation data to assess lack of co-segregation.
BP5 No tumor data are available for NM_000179.3:c.260+21T>G. The InSiGHT MSH6 VCEP v2.0.0 requires MSS tumors, absence of MMR protein expression loss, or BRAF V600E/MLH1 methylation data. None have been identified for this variant. Details ▾Hide ▴
Still missing
- No tumor MSS/MMR IHC/BRAF/MLH1 methylation data available.
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis intronic variant at c.260+21 (intron 1, +21 position) does not qualify for PVS1 under the InSiGHT MSH6 VCEP v2.0.0: it is not a nonsense/frameshift variant introducing a PTC ≤ codon 1341, not a canonical splice site variant (±1, ±2), not a large genomic alteration, and no mRNA splicing aberration has been confirmed by patient RNA assays. Details ▾Hide ▴
Evidence considered
- VCEP PVS1 rules require null variant classes or confirmed splicing aberration
- c.260+21T>G is a deep intronic substitution with no splicing defect confirmed.
Sources
PS1 N/APS1 under the InSiGHT MSH6 VCEP v2.0.0 applies only to missense variants encoding the same amino acid change as a known pathogenic variant, or variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant. This intronic substitution at c.260+21 does not change an amino acid and no pathogenic variant has been established at this intronic position. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rules are restricted to missense same-AA-change or same non-canonical splice nucleotide with pathogenic comparator
- neither applies here.
Sources
PS4 VCEPPS4 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0 and is not used in this framework. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
PM1 VCEPPM1 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0 as no mutational hotspot or critical functional domain criteria are specified for this gene. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
PM5 N/APM5 applies only to missense changes at an amino acid residue where a different missense change has been classified as pathogenic/likely pathogenic. This variant is an intronic substitution and does not alter an amino acid residue. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.260+21)
- not a missense change
- PM5 candidate search returned no eligible comparators.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0; de novo evidence is assessed under PS2 instead. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6 (de novo assessed under PS2).
Sources
PP2 VCEPPP2 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0; missense variants in a gene with low rate of benign missense changes does not apply. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
PP5 VCEPPP5 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0 and is not used in this framework. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
BP1 VCEPBP1 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0; this criterion (missense variant in a gene where primarily truncating variants cause disease) is not used for MSH6. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
BP2 VCEPBP2 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0 and is not used in this framework. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
BP3 VCEPBP3 is skipped per directive: this is a substitution variant, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is declared Not Applicable by the InSiGHT MSH6 VCEP v2.0.0; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- Criterion explicitly marked Not Applicable in the CSPEC/VCEP specification for MSH6.
Sources
PS5 N/APS5 is not defined in the InSiGHT MSH6 VCEP v2.0.0 criteria set and is not used in this framework. Details ▾Hide ▴
Identifiers
- Gene
- MSH6
- Transcript
- NM_000179.3
- Coding (HGVS c.)
- NM_000179.3:c.260+21T>G
- Protein (HGVS p.)
- NP_000170.1:p.?
- GRCh38
- chr2:47783514 T>G
- GRCh37
- chr2:48010653 T>G
- ClinVar
- 491905
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
6 / 1,388,350 alleles
AF 4.32e-06 · 0 homozygotes · FAF 1.1e-05
gnomAD v2.1
0 / 34,192 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 6 / 1,388,350 alleles · 0 hom · FAF 1.1e-05
| Admixed American2 / 29,988 | 6.7e-05 |
| African/African American1 / 62,352 | 1.6e-05 |
| European (non-Finnish)3 / 1,069,618 | 2.8e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0 · 0 / 34,192 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.32168e-06; MAF= 0.00043%, 6/1388350 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.66933e-05; MAF= 0.00667%, 2/29988 alleles, homozygotes = 0); grpmax FAF= 1.104e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/34192 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/852 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingUnder the InSiGHT MSH6 VCEP v2.0.0, BP4_Supporting is met for intronic variants when SpliceAI predicts no splicing impact with delta score ≤ 0.1. SpliceAI predicts no significant splice impact for NM_000179.3:c.260+21T>G (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- meeting the VCEP BP4_Supporting threshold of ≤ 0.1 for intronic variants.
Sources
BP7 SupportingUnder the InSiGHT MSH6 VCEP v2.0.0, BP7_Supporting applies to intronic variants at or beyond -21/+7 from the exon boundary. NM_000179.3:c.260+21T>G is located at position +21 in intron 1, which is beyond the +7 threshold, satisfying the VCEP BP7 rule. Details ▾Hide ▴
Evidence considered
- Variant is intronic at position +21
- beyond the VCEP BP7 threshold of +7 from the exon boundary.
Sources
PP3 Under the InSiGHT MSH6 VCEP v2.0.0, PP3 applies to (a) missense variants with HCI prior >0.68, or (b) intronic/splice variants with SpliceAI delta score ≥ 0.2. This is an intronic variant and SpliceAI predicts no splicing impact (max delta score = 0.00), falling below the 0.2 threshold. The variant is not missense and has no HCI prior score. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (below PP3 threshold of 0.2)
- HCI prior not applicable (intronic variant not in missense lookup table).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
2 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
-
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 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
6 / 1,388,350 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
1 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/491905/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-48010653-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47783514-T-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000179.3%3Ac.260%…
- OncoKB ↗www.oncokb.org/gene/MSH6/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH6+c.260+21T%3EG
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= 4.32168e-06; MAF= 0.00043%, 6/1388350 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.66933e-05; MAF= 0.00667%, 2/29988 alleles, homozygotes = 0); grpmax FAF= 1.104e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/34192 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/852 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 491905)
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).