MSH6

Final classification

Pathogenic

PVS1PM2PP4PP5

MSH6

c.2731C>T

p.Arg911Ter

nonsense · exon 4

Gene context NCBI Gene ↗ OncoKB ↗

MSH6 encodes a protein in the DNA mismatch repair system, which fixes errors made during DNA replication. Partnering with MSH2, it forms a complex that recognizes and helps correct mismatched DNA bases, keeping the genetic code stable. Inherited mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), raising the risk of colorectal, endometrial, ovarian, and other cancers, while mutations in both copies lead to constitutional mismatch repair deficiency. Because faulty mismatch repair drives tumor development and produces microsatellite instability, MSH6 acts as a tumor suppressor, and cancers with such repair defects often respond well to immune checkpoint inhibitor therapy.

This variant

This Pathogenic MSH6 variant, p.Arg911Ter, is expected to disrupt DNA mismatch repair, the pathway that protects genomic stability. Inherited pathogenic MSH6 variants are associated with Lynch syndrome and increased colorectal, endometrial, ovarian, and other cancer risks.

Transcript

NM_000179.3

HGVS · transcript:coding

NM_000179.3:c.2731C>T

GRCh38

chr2:47800714 C>T

GRCh37

chr2:48027853 C>T

Basis Pathogenic: PVS1 Very Strong plus PM2 Supporting, PP4 Moderate, and PP5 Supporting satisfies the MSH6 VCEP Rule 4 combination. ▾

Pathogenic: PVS1 Very Strong plus PM2 Supporting, PP4 Moderate, and PP5 Supporting satisfies the MSH6 VCEP Rule 4 combination.

Classification rationale

PVS1PM2PP4PP5 Pathogenic

MSH6 c.2731C>T nonsense · exon 4

PVS1 (Very Strong): Nonsense variant p.Arg911Ter creates a premature stop codon before the MSH6 codon 1341 cutoff. PM2 (Supporting): gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00002 threshold. PP4 (Moderate): This exact variant occurred in two independent endometrial cancer tumors that were MSI-H. PP5 (Supporting): The InSiGHT expert panel classified this exact variant as Pathogenic. Overall classification: Pathogenic under MSH6 VCEP Rule 4, combining one Very Strong criterion with at least two Supporting criteria.

PVS1 + PM2 + PP4 + PP5 → Pathogenic

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 11 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met (Very Strong): Nonsense variant p.Arg911Ter creates a premature stop codon before the MSH6 codon 1341 cutoff.

The MSH6 Version 2.0 VCEP rule specifies PVS1 Very Strong for a nonsense or frameshift variant introducing a premature termination codon at or before codon 1341 in MSH6.The case variant is NM_000179.3:c.2731C>T with the predicted protein consequence NP_000170.1:p.(Arg911Ter); codon 911 is below the VCEP cutoff of 1341.The ClinVar source record identifies the exact variant as NM_000179.3(MSH6):c.2731C>T (p.Arg911Ter), supporting transcript and protein-consequence relevance without relying on ClinVar's final classification.

cspec ↗clinvar ↗

✓

PM2 supporting Pathogenic

Met (Supporting): gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00002 threshold.

The MSH6 InSiGHT VCEP Version 2.0 specifies PM2_Supporting for an absent or extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.gnomAD v4.1 reports total AF 1.36314e-05 (22/1,613,924 alleles), Grpmax FAF 8.78e-06, and zero observed homozygotes.

cspec ↗gnomad_v4 ↗

✓

PP4 moderate Pathogenic

Met (Moderate): This exact variant occurred in two independent endometrial cancer tumors that were MSI-H.

The MSH6 VCEP specifies PP4_Moderate for two independent CRC or endometrial MSI-H tumors using a standard 5-10 marker panel or tumor genome and/or MMR-protein loss consistent with the variant location.Goodfellow et al. reported the exact C>T substitution at codon 911 (c.2731C>T, Arg→Stop) in endometrial cancer patients 1335 and 1497; both were among the germline MSH6 mutation carriers with MSI-positive cancers, and the paper states that all probands' cancers had high-level MSI.Buttin et al. reported the exact R911Z mutation in MSH6 kindreds 1335 and 1497 and stated that all probands' cancers had high-level MSI; the study used MSI testing and MMR-protein immunohistochemistry.

cspec ↗PMID:12732731 ↗PMID:15098177 ↗

✓

PP5 supporting Pathogenic

Met (Supporting): The InSiGHT expert panel classified this exact variant as Pathogenic.

The ClinVar record exactly matches NM_000179.3(MSH6):c.2731C>T (p.Arg911Ter) and reports Pathogenic reviewed by expert panel (three stars), with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) identified as the expert panel.Only the exact-variant expert-panel classification was used for PP5; clinical-laboratory submissions, non-expert assertions, and the aggregate label were not independently treated as PP5 evidence.ClinVar expert panel classification

clinvar ↗

Assessed · not applied · 4 not met · 7 not assessed

Pathogenic

PS2 Not assessed: No parental testing, confirmed de novo status, or qualifying tumor evidence was available.

PS3 Not assessed: No variant-specific functional assay or calibrated functional odds were available.

PM3 Not assessed: No second pathogenic MSH6 variant, phase information, or qualifying CMMRD features were available.

PP1 Not assessed: No variant-specific pedigree, cosegregation data, or Bayes likelihood ratio was available.

PP3 Not met: SpliceAI maximum delta score is 0.005, below the required >=0.2 splice-impact threshold.

Benign

BA1 Not met: gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.0022 threshold.

BS1 Not met: gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00022 threshold.

BS2 Not assessed: No confirmed in-trans pathogenic variant, phase, cancer history, or CMMRD-exclusion evidence was available.

BS3 Not assessed: No variant-specific functional assay or calibrated evidence of proficient function was available.

BS4 Not assessed: No variant-specific non-segregation observations, pedigree data, or Bayes likelihood ratio was available.

BP5 Not met: No qualifying MSS or MMR-retained tumors were identified; reported tumors were MSI-H.

N/A · 13 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.36314e-05; MAF= 0.00136%, 22/1613924 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80108e-05; MAF= 0.00480%, 3/62486 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48256e-05; MAF= 0.00648%, 1/15426 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 22 / 1,613,924
0 hom · FAF 0.00088%

Remaining individuals 3 / 62,486	0.0048%
European (Finnish) 1 / 64,000	0.0016%
European (non-Finnish) 17 / 1,180,004	0.0014%
South Asian 1 / 91,072	0.0011%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0032% · 1 / 31,398
0 hom

European (non-Finnish)

1 / 15,426

0.0065%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (27 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89312)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.512542.

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52274832, n = 7 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers.

PMID 12732731 ↗ CLINVAR · functional

Searched

c.2731C>Tp.Arg911TerR911*codon 911MSI-HMSS

Found

In an unselected series of 441 endometrial cancers, 100 tumors were evaluated for MSH6 defects and seven germline MSH6 mutations were identified in women with MSI-positive, MLH1-unmethylated cancers. The paper specifically reports a single-base C>T substitution at codon 911 (c.2731C>T) in patients 1335 and 1497, both with MSI-H endometrial cancers.

Variant

✓ Names this variant — characterised directly

Applied to

→PP4 moderate

The exact c.2731C>T variant is reported in two endometrial-cancer patients with MSI-H tumors, supporting PP4_Moderate under the MSH6 VCEP rule.

Single base C 3 T substitution at codon 911 in patient 1497. Reverse sequence is shown (G 3 A). ... 1335 ... 911 ... C3T at 2731 ... Arg3Stop ... 1497† ... 911 ... C3T at 2731 ... Arg3Stop

Location Results and Discussion, Germ-Line Mutations; Figure 3 and Table 2, pp. 5910-5911 · Context Prospective/unselected endometrial-cancer cohort; MSI assessed with the five consensus markers BAT25, BAT26, D5S346, D2S123, and D17S250; MLH1 promoter methylation assessed in MSI-positive tumors; germline MSH6 mutation analysis performed by SSCV and direct sequencing. · full text

Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history.

PMID 15098177 ↗ · Buttin BM et al. · 2004 Jun CLINVAR · functional

Searched

c.2731C>TR911ZR911*MSI-Hendometrial cancerMSS

Found

This study of seven MSH6 kindreds identified the exact R911Z loss-of-function mutation in kindreds 1335 and 1497. It states that all probands' cancers had high-level MSI and provides tumor MSI and MMR-protein immunohistochemistry data, supporting phenotype specificity for the exact variant in endometrial-cancer probands.

Variant

✓ Names this variant — characterised directly

Applied to

→PP4 moderate

The exact R911Z mutation occurs in two MSH6 kindreds with proband cancers reported as high-level MSI, supporting PP4_Moderate under the MSH6 VCEP rule.

The loss-of-function mutations in these kindreds are as follows ... 1335 R911Z; 1497 R911Z ... All of the probands’ cancers had high-level microsatellite instability (MSI-H).

Location Introduction to study cohort and mutation list, p. 1263 · Context Seven kindreds ascertained through endometrial-cancer probands; detailed pedigrees and confirmed cancer histories; tumor MSI analysis using consensus markers and additional BAT40; immunohistochemistry for MSH2, MLH1, and MSH6. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

24362816 ↗ Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. ONCOKB

1651234 ↗ Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities. ONCOKB

22810696 ↗ Comprehensive molecular characterization of human colon and rectal cancer. ONCOKB

24755471 ↗ Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. ONCOKB

9111312 ↗ Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition. ONCOKB

32720330 ↗ Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. CLINVAR