MSH6c.4002-28_4002-26dupBenign

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Variant interpretation report

MSH6 c.4002-28_4002-26dup, p.?

NM_000179.3:c.4002-28_4002-26dup NP_000170.1:p.? View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MSH6

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 stand alone (benign) · 2 supporting (benign)
Expert rules: ClinGen MSH6 VCEP v2.0.0
Other laboratories (ClinVar): 2 Benign · 1 Likely benign
Pipeline record: 15 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

BA1 (stand alone): gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP BA1 stand-alone threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1. Highest frequency in the East Asian population (2.83% in v4, 3.14% in v2). No evidence this is a founder pathogenic variant.
BP4 (supporting): SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 per Walker et al. 2023.
BP7 (supporting): Intronic duplication located at positions -26 and -28 relative to exon 10, which is at or beyond the VCEP BP7 threshold of -21. SpliceAI predicts no splicing impact (max delta = 0.00).

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: 3

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3

BA1Stand alone

BA1 · stand alone

gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP BA1 stand-alone threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1. Highest frequency in the East Asian population (2.83% in v4, 3.14% in v2). No evidence this is a founder pathogenic variant.

BP4Supporting

BP4 · supporting

SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 per Walker et al. 2023.

BP7Supporting

BP7 · supporting

Intronic duplication located at positions -26 and -28 relative to exon 10, which is at or beyond the VCEP BP7 threshold of -21. SpliceAI predicts no splicing impact (max delta = 0.00).

Recorded classification: 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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting benign, BP7 supporting benign; maps to 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

1,883 / 1,403,604 alleles

gnomAD v4.1: 1,883 / 1,403,604 alleles. Recorded AF 0.00134155. Recorded homozygote count 6.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00252012; MAF= 0.25201%, 570/226180 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.0313601; MAF= 3.13601%, 445/14190 alleles, homozygotes = 2); grpmax FAF= 0.0565538.

Applied · BA1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

2 Benign · 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.

28 criteria with recorded statuses: 3 met · 12 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

BA1 is met at stand-alone strength: gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1, and is not a known founder pathogenic variant.

BP7 is met at supporting benign strength: the variant is an intronic duplication at positions -26 to -28 relative to exon 10, which is beyond the VCEP BP7 threshold of -21.

BP4 is met at supporting benign strength: SpliceAI predicts no splicing impact (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 for intronic variants.

Per the InSiGHT MSH6 VCEP v2.0.0 combination rules, BA1 stand-alone alone is sufficient for a Benign classification (Rule 17).

Met · 3

BA1 Stand alonegnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP BA1 stand-alone threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1. Highest frequency in the East Asian population (2.83% in v4, 3.14% in v2). No evidence this is a founder pathogenic variant. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 0.027 (2.70%)
gnomAD v2.1 grpmax FAF = 0.057 (5.66%)
gnomAD v4.1: 6 homozygotes
gnomAD v2.1: 2 homozygotes
VCEP BA1 threshold: ≥0.0022 (0.22%)
Excluded as founder pathogenic variant: no evidence of founder pathogenicity

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 per Walker et al. 2023. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00
VCEP BP4_Supporting threshold: SpliceAI delta ≤ 0.1 for intronic variants

Sources

spliceai ↗cspec ↗

BP7 SupportingIntronic duplication located at positions -26 and -28 relative to exon 10, which is at or beyond the VCEP BP7 threshold of -21. SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴

Evidence considered

Variant position: c.4002-28_4002-26 (intronic
beyond -21 from exon boundary)
SpliceAI max delta = 0.00
VCEP BP7 rule: intronic variant at or beyond -21/+7

Sources

spliceai ↗cspec ↗

Not met · 12 · evaluated, threshold not reached

PVS1 Intronic duplication at c.4002-28_4002-26 (26-28 nucleotides upstream of exon 10 in MSH6 intron 9). Does not affect a canonical splice donor/acceptor site and is not predicted to alter splicing (SpliceAI max delta = 0.00). Does not fall into any VCEP PVS1 strength category (nonsense/frameshift, large genomic alteration, IVS±1,2, or patient mRNA-confirmed splicing aberration). Details ▾Hide ▴

Evidence considered

SpliceAI predicts no splicing impact (max delta = 0.00)
Variant is intronic
not at canonical ±1
2 splice consensus
Variant bucket classified as 'other' by generic PVS1 framework

Sources

spliceai ↗

PS2 No de novo observations have been reported for this variant in any database or literature. Details ▾Hide ▴

Evidence considered

No de novo reports identified in ClinVar
gnomAD
or published literature

PS3 No calibrated functional assay data available for this variant. No patient mRNA or minigene splicing assay demonstrating a damaging effect has been reported. The functional assay SVI documentation spreadsheet does not list this variant. Details ▾Hide ▴

Evidence considered

Variant absent from VCEP calibrated functional assay documentation
SpliceAI delta = 0.00 does not support a damaging splice effect

Sources

2574186825394175

PM2 Variant is present in gnomAD v4.1 at an allele frequency of 0.134% (1883/1403604 alleles, 6 homozygotes), far exceeding the VCEP PM2_Supporting threshold of <0.002% (<1 in 50,000 alleles). Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF=0.134%
1883 alleles
6 homozygotes
gnomAD v2.1 AF=0.252%
570 alleles
2 homozygotes
VCEP PM2 threshold: <0.002%

Sources

gnomad_v4 ↗gnomad_v2 ↗

PP1 No co-segregation data available for this variant. No pedigrees with formal Bayes likelihood ratio analysis have been reported. Details ▾Hide ▴

Evidence considered

No segregation data found in ClinVar
LOVD
or published literature

PP3 SpliceAI predicts no splicing impact (max delta score = 0.00), below the VCEP PP3_Supporting threshold of ≥0.2 for non-canonical splice variants. HCI prior is not applicable for this non-missense variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (<0.2 threshold)
HCI prior not applicable (intronic duplication
not missense)

Sources

spliceai ↗

PP4 No tumor phenotype data (MSI status, IHC for MMR protein expression) have been reported for patients carrying this variant. Details ▾Hide ▴

Evidence considered

No MSI-H tumor data available
No MMR IHC data available

BS1 gnomAD v4.1 grpmax FAF is 0.027 (2.70%), which exceeds the VCEP BS1 upper bound of <0.0022 (0.22%). The variant frequency is too high for BS1 and is captured by BA1 instead. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 0.027 > 0.0022 BS1 upper bound
VCEP BS1 range: 0.00022 to <0.0022

Sources

gnomad_v4 ↗cspec ↗

BS2 No data demonstrating co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. Details ▾Hide ▴

Evidence considered

No trans co-occurrence data available

BS3 No laboratory functional assay data available demonstrating no splicing aberration or proficient MMR function. The VCEP BS3 rule for intronic variants requires mRNA aberration assessment by laboratory assays conducted with NMD inhibition; in silico SpliceAI prediction alone is insufficient. This variant is not listed in the VCEP calibrated functional assay documentation. Details ▾Hide ▴

Evidence considered

SpliceAI delta = 0.00 predicts no splicing impact (in silico only)
Variant absent from VCEP functional assay SVI documentation
No patient mRNA or minigene assay data available

Still missing

No laboratory mRNA assay data with NMD inhibition confirming absence of splicing aberration

Sources

spliceai ↗2574186825394175

BS4 No segregation data available to evaluate lack of co-segregation with disease. Details ▾Hide ▴

Evidence considered

No segregation data found in any source

BP5 No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, MLH1 methylation) available for patients carrying this variant. Details ▾Hide ▴

Evidence considered

No tumor data available

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/AVariant is an intronic duplication, not a missense substitution and not affecting a non-canonical splice nucleotide with a known pathogenic comparator. Details ▾Hide ▴

Identifiers

Gene: MSH6
Transcript: NM_000179.3
Coding (HGVS c.): NM_000179.3:c.4002-28_4002-26dup
Protein (HGVS p.): NP_000170.1:p.?
GRCh38: chr2:47806750 A>ACTT
GRCh37: chr2:48033889 A>ACTT
ClinVar: 926536

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1,883 / 1,403,604 alleles AF 0.00134 · 6 homozygotes · FAF 0.027

gnomAD v2.1 570 / 226,180 alleles AF 0.00252 · 2 homozygotes · FAF 0.0566

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0.0013 · 1883 / 1,403,604 alleles · 6 hom · FAF 0.027

East Asian1159 / 40,910	0.0285 hom
African/African American143 / 59,072	0.00241 hom
Remaining individuals127 / 55,562	0.0023
Admixed American83 / 55,138	0.0015
South Asian81 / 83,322	0.00097
Middle Eastern4 / 5,610	0.00071
European (non-Finnish)283 / 1,016,204	0.00028
European (Finnish)3 / 58,906	5.1e-05

0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0025 · 570 / 226,180 alleles · 2 hom · FAF 0.057

East Asian445 / 14,190	0.0312 hom
African/African American57 / 18,028	0.0032
Remaining individuals12 / 5,958	0.002
Admixed American27 / 30,310	0.00089
South Asian12 / 25,840	0.00046
European (non-Finnish)16 / 102,806	0.00016
European (Finnish)1 / 20,050	5e-05

0 alternate alleles recorded in 1 other group: Ashkenazi Jewish.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00134155; MAF= 0.13415%, 1883/1403604 alleles, homozygotes = 6) and has highest observed frequency in the East Asian population (AF= 0.0283305; MAF= 2.83305%, 1159/40910 alleles, homozygotes = 5); grpmax FAF= 0.0269749.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.070

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 per Walker et al. 2023. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00
VCEP BP4_Supporting threshold: SpliceAI delta ≤ 0.1 for intronic variants

Sources

spliceai ↗cspec ↗

Evidence considered

Variant position: c.4002-28_4002-26 (intronic
beyond -21 from exon boundary)
SpliceAI max delta = 0.00
VCEP BP7 rule: intronic variant at or beyond -21/+7

Sources

spliceai ↗cspec ↗

Evidence considered

SpliceAI max delta = 0.00 (<0.2 threshold)
HCI prior not applicable (intronic duplication
not missense)

Sources

spliceai ↗

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

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. · 2015

No paper-specific finding is recorded.

PMID 25741868 ↗
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. · 2015

No paper-specific finding is recorded.

PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1,883 / 1,403,604 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 2 Benign · 1 Likely benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 926536)

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).