MSH6c.1135_1139delPathogenic

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Variant interpretation report

MSH6 c.1135_1139del, p.(Arg379Ter)

NM_000179.3:c.1135_1139del NP_000170.1:p.(Arg379Ter) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic 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 very strong (pathogenic) · 1 moderate (pathogenic) · 3 supporting (pathogenic)
Expert rules: ClinGen MSH6 VCEP v2.0.0
Other laboratories (ClinVar): 20 Pathogenic · 1 Uncertain significance
Pipeline record: 11 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000179.3:c.1135_1139del is a 5-bp deletion in exon 4 of MSH6 that introduces a premature termination codon at p.Arg379Ter. Under the InSiGHT/ClinGen MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 meet PVS1 at Very Strong strength. The PTC at codon 379 lies well within this boundary, and loss of function is an established disease mechanism for MSH6 in Lynch syndrome.
PS2 (supporting): PMID 37318702 reports this variant as a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* variant in a patient with MSH6-deficient endometrial and colorectal cancer. The variant was detected at low mosaic levels in blood (1.64%), saliva (3.49%), and normal colonic tissue (5.34%), indicating early embryonic occurrence consistent with de novo origin. Under the MSH6 VCEP PS2 scoring system, a proband with a de novo variant without confirmed parental testing but clinically likely de novo and with MMR-deficient LS spectrum tumors receives 0.5 points, meeting PS2_Supporting.
PM2 (supporting): In gnomAD v4.1, this variant has an allele frequency of 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), which is below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). In gnomAD v2.1, it has an AF of 3.98e-06 (1/250,986 alleles). No homozygotes are observed in either dataset. This meets PM2_Supporting per the MSH6 VCEP.
PP4 (moderate): The case report in PMID 37318702 describes a patient with two independent MSH6-deficient tumors: endometrial cancer at age 54 and colorectal cancer at age 58. Both tumors showed loss of MSH6 protein expression consistent with the variant location. Under the MSH6 VCEP, 2 independent CRC/Endometrial tumors with loss of MMR protein expression consistent with the variant location meets PP4_Moderate.
PP5 (supporting): Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

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: 5 Benign evidence criteria: 0

Pathogenic criteria applied · 5

PVS1Very strong

PVS1 · very strong

NM_000179.3:c.1135_1139del is a 5-bp deletion in exon 4 of MSH6 that introduces a premature termination codon at p.Arg379Ter. Under the InSiGHT/ClinGen MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 meet PVS1 at Very Strong strength. The PTC at codon 379 lies well within this boundary, and loss of function is an established disease mechanism for MSH6 in Lynch syndrome.

PS2Supporting

PS2 · supporting

PMID 37318702 reports this variant as a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* variant in a patient with MSH6-deficient endometrial and colorectal cancer. The variant was detected at low mosaic levels in blood (1.64%), saliva (3.49%), and normal colonic tissue (5.34%), indicating early embryonic occurrence consistent with de novo origin. Under the MSH6 VCEP PS2 scoring system, a proband with a de novo variant without confirmed parental testing but clinically likely de novo and with MMR-deficient LS spectrum tumors receives 0.5 points, meeting PS2_Supporting.

PM2Supporting

PM2 · supporting

In gnomAD v4.1, this variant has an allele frequency of 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), which is below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). In gnomAD v2.1, it has an AF of 3.98e-06 (1/250,986 alleles). No homozygotes are observed in either dataset. This meets PM2_Supporting per the MSH6 VCEP.

PP4Moderate

PP4 · moderate

The case report in PMID 37318702 describes a patient with two independent MSH6-deficient tumors: endometrial cancer at age 54 and colorectal cancer at age 58. Both tumors showed loss of MSH6 protein expression consistent with the variant location. Under the MSH6 VCEP, 2 independent CRC/Endometrial tumors with loss of MMR protein expression consistent with the variant location meets PP4_Moderate.

PP5Supporting

PP5 · supporting

Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

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 Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PS2 supporting, PM2 supporting, PP4 moderate, PP5 supporting; maps to Pathogenic.

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

4 / 1,614,148 alleles

gnomAD v4.1: 4 / 1,614,148 alleles. Recorded AF 2.47809e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98429e-06; MAF= 0.00040%, 1/250986 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82394e-06; MAF= 0.00088%, 1/113328 alleles, homozygotes = 0).

Applied · PM2 →

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

SpliceAI score

0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

21 reported laboratory submissions

20 Pathogenic · 1 Uncertain significance.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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

COSMIC ↗Cancer Hotspots ↗

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: 5 met · 4 not met · 5 not assessed · 14 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

PVS1_Very_Strong: NM_000179.3:c.1135_1139del introduces a premature termination codon at p.Arg379Ter, well within the VCEP boundary of codon 1341. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.

PM2_Supporting: This variant is extremely rare in population databases. In gnomAD v4.1, allele frequency is 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), below the VCEP threshold of <0.00002.

PP4_Moderate: The variant has been observed in a patient with two independent MSH6-deficient tumors (endometrial cancer at age 54 and colorectal cancer at age 58), meeting VCEP criteria for 2 independent tumors with IHC loss consistent with the variant gene.

PS2_Supporting: The variant was identified as a likely de novo mosaic variant detectable across all three germ layers in a patient with MSH6-deficient Lynch spectrum tumors, meeting 0.5 de novo points under the VCEP PS2 scoring system.

Combining 1 Very Strong (PVS1) + 2 Supporting (PM2 + PS2) satisfies VCEP Rule 4 (1 VS + >=2 Sup → Pathogenic). The additional Moderate criterion (PP4) further supports the pathogenic classification.

Met · 5

PVS1 Very strongNM_000179.3:c.1135_1139del is a 5-bp deletion in exon 4 of MSH6 that introduces a premature termination codon at p.Arg379Ter. Under the InSiGHT/ClinGen MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 meet PVS1 at Very Strong strength. The PTC at codon 379 lies well within this boundary, and loss of function is an established disease mechanism for MSH6 in Lynch syndrome. Details ▾Hide ▴

Evidence considered

MSH6 loss-of-function is an established mechanism for Lynch syndrome (CSPEC/VCEP confirmed)
5-bp deletion creates frameshift introducing PTC at codon 379
PTC position 379 ≤ 1341 meets VCEP PVS1 Very Strong threshold

Sources

pvs1_gene_contextpvs1_variant_assessmentcspec ↗clinvar ↗

PS2 SupportingPMID 37318702 reports this variant as a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* variant in a patient with MSH6-deficient endometrial and colorectal cancer. The variant was detected at low mosaic levels in blood (1.64%), saliva (3.49%), and normal colonic tissue (5.34%), indicating early embryonic occurrence consistent with de novo origin. Under the MSH6 VCEP PS2 scoring system, a proband with a de novo variant without confirmed parental testing but clinically likely de novo and with MMR-deficient LS spectrum tumors receives 0.5 points, meeting PS2_Supporting. Details ▾Hide ▴

Evidence considered

PMID 37318702: likely de novo mosaic MSH6:c.1135_1139del in patient with MSH6-deficient EC and CRC
Variant detected across all three germ layers confirming early embryonic origin
Meets VCEP PS2 0.5-point threshold for de novo without parental confirmation

Still missing

Parental confirmation of de novo status was not performed
variant is mosaic

Sources

37318702

PM2 SupportingIn gnomAD v4.1, this variant has an allele frequency of 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), which is below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). In gnomAD v2.1, it has an AF of 3.98e-06 (1/250,986 alleles). No homozygotes are observed in either dataset. This meets PM2_Supporting per the MSH6 VCEP. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 2.48e-06 (4/1
614
148)
grpmax FAF = 7.9e-07
gnomAD v2.1 AF = 3.98e-06 (1/250
986)
Frequencies well below VCEP PM2_Supporting threshold of <0.00002
No homozygotes observed

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP4 ModerateThe case report in PMID 37318702 describes a patient with two independent MSH6-deficient tumors: endometrial cancer at age 54 and colorectal cancer at age 58. Both tumors showed loss of MSH6 protein expression consistent with the variant location. Under the MSH6 VCEP, 2 independent CRC/Endometrial tumors with loss of MMR protein expression consistent with the variant location meets PP4_Moderate. Details ▾Hide ▴

Evidence considered

PMID 37318702: patient developed MSH6-deficient EC at age 54 and CRC at age 58
Both tumors showed MSH6 protein loss consistent with variant location
Meets VCEP PP4_Moderate: 2 independent MSI-H/MSH6-deficient tumors

Sources

37318702

PP5 SupportingExpert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

PP3 PP3 under the MSH6 VCEP requires either (a) a missense variant with HCI prior probability >0.68, or (b) a non-canonical splice variant with SpliceAI delta score ≥0.2. This variant is not a missense substitution (HCI prior lookup returned no result), and SpliceAI predicts no significant splicing impact (max delta score = 0.03). PP3 is not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.03 (below VCEP PP3 threshold of 0.2)
Not a missense variant
HCI prior not applicable

Sources

spliceai ↗

BA1 The MSH6 VCEP BA1 threshold is gnomAD v4 grpmax FAF ≥ 0.0022 (0.22%). This variant has a grpmax FAF of 7.9e-07 (0.000079%), far below the BA1 threshold. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 7.9e-07 (0.000079%)
Far below VCEP BA1 threshold of ≥0.22%

Sources

gnomad_v4 ↗

BS1 The MSH6 VCEP BS1 threshold is gnomAD v4 grpmax FAF ≥ 0.00022 (0.022%) and < 0.0022. This variant has a grpmax FAF of 7.9e-07 (0.000079%), below the BS1 threshold. BS1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 7.9e-07 (0.000079%)
Below VCEP BS1 threshold of ≥0.022%

Sources

gnomad_v4 ↗

BP5 BP5 requires tumors showing MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in MSI-H tumors. The evidence from PMID 37318702 shows the opposite: both tumors (EC and CRC) were MSH6-deficient with loss of MSH6 protein expression, consistent with pathogenicity. BP5 is not met. Details ▾Hide ▴

Evidence considered

Both tumors showed MSH6-deficient IHC
inconsistent with BP5 requirements

Sources

37318702

Not assessed · 5 · no assessment recorded

PS3 No calibrated functional assay data (functional odds for pathogenicity) is available for this specific variant in the VCEP functional assay SVI documentation. OncoKB assigns a Likely Loss-of-function label based on the predicted truncating nature, but this is not empirical functional evidence meeting VCEP PS3 calibrated assay thresholds. Details ▾Hide ▴

Evidence considered

OncoKB notes predicted loss-of-function effect
but no calibrated functional odds available
Variant not listed in VCEP Functional-assay-SVI-documentation-MMR.xlsx

Still missing

No calibrated functional assay data available for this specific variant
No MMR functional assay results in the literature for c.1135_1139del

Sources

oncokb ↗

PP1 No co-segregation data (Bayes Likelihood Ratio from pedigrees) is available for this variant in the evidence collected. PP1 requires formal segregation analysis with combined Bayes LR meeting VCEP thresholds (>2.08, >4.3, or >18.7). Details ▾Hide ▴

Still missing

No pedigree co-segregation data or formal Bayes LR analysis available

BS2 BS2 under the MSH6 VCEP requires observation of the variant in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features, with confirmed phase. No such co-occurrence data was identified in the evidence collected. Details ▾Hide ▴

Still missing

No in trans co-occurrence data with a known pathogenic MSH6 variant available

BS3 No calibrated functional assay data demonstrating proficient MMR function (functional odds for pathogenicity ≤0.05 or >0.05 & ≤0.48) is available for this specific variant. The VCEP functional assay SVI documentation does not list this variant. Details ▾Hide ▴

Evidence considered

Variant not listed in VCEP Functional-assay-SVI-documentation-MMR.xlsx

Still missing

No calibrated functional assay data available for BS3 evaluation

Sources

vcep_functional_assay_svi_documentation_mmr

BS4 BS4 under the MSH6 VCEP requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting VCEP thresholds. No segregation data is available for this variant. Details ▾Hide ▴

Still missing

No pedigree segregation data available

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 under the MSH6 VCEP applies to missense substitutions encoding the same amino acid change as a previously established Pathogenic/Likely Pathogenic variant, or to splice-site variants affecting the same non-canonical nucleotide. This variant is a frameshift/nonsense variant and does not fall under PS1 applicability. Details ▾Hide ▴

BP6 VCEPBP6 is explicitly listed as Not Applicable for this VCEP by the MSH6 VCEP v2.0.0, per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/ABP7 under the MSH6 VCEP applies to synonymous (silent) or intronic variants at or beyond -21/+7. This is a frameshift/nonsense variant and does not fall under BP7 applicability. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 (reputable source reports variant as pathogenic) is not an applicable criterion under the MSH6 VCEP v2.0.0; the VCEP explicitly makes PP5 and BP6 (which together cover the reputable-source domain) Not Applicable. Details ▾Hide ▴

Sources

cspec ↗

Identifiers

Gene: MSH6
Transcript: NM_000179.3
Coding (HGVS c.): NM_000179.3:c.1135_1139del
Protein (HGVS p.): NP_000170.1:p.(Arg379Ter)
GRCh38: chr2:47799111 AAAGAG>A
GRCh37: chr2:48026250 AAAGAG>A
ClinVar: 89174, 428442

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 4 / 1,614,148 alleles AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07

gnomAD v2.1 1 / 250,986 alleles AF 3.98e-06 · 0 homozygotes

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

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,614,148 alleles · 0 hom · FAF 7.9e-07

European (non-Finnish)4 / 1,180,022

3.4e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 250,986 alleles · 0 hom

European (non-Finnish)1 / 113,328

8.8e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.47809e-06; MAF= 0.00025%, 4/1614148 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38977e-06; MAF= 0.00034%, 4/1180022 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -500 bp

0.020

SpliceAI acceptor gainat +284 bp

0.000

SpliceAI donor lossat +156 bp

0.030

SpliceAI donor gainat -219 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.03 (below VCEP PP3 threshold of 0.2)
Not a missense variant
HCI prior not applicable

Sources

spliceai ↗

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

8 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

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA et al. · 2014

No paper-specific finding is recorded.

PMID 24362816 ↗
Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities.

No paper-specific finding is recorded.

PMID 1651234 ↗
Comprehensive molecular characterization of human colon and rectal cancer.

No paper-specific finding is recorded.

PMID 22810696 ↗
Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.

No paper-specific finding is recorded.

PMID 24755471 ↗
Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition.

No paper-specific finding is recorded.

PMID 9111312 ↗
hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha.

No paper-specific finding is recorded.

PMID 9564049 ↗
Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism.

No paper-specific finding is recorded.

PMID 9822680 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

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

gnomAD v4.1 4 / 1,614,148 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗

ClinVar 20 Pathogenic · 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

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 Pathogenic (20 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89174)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.