# NM_000179.3(MSH6):c.1933del (p.Glu645fs)

https://sugi.bio/variant/msh6-p-glu645fs

## Summary

**MSH6 p.Glu645fs (c.1933del)** is classified **Pathogenic/Likely pathogenic** in MSH6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-09). No gnomAD frequency available for this variant; Associated with Lynch syndrome 5.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1558663559 · 4 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MSH6 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to Lynch syndrome 5.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | MSH6 is a diagnostic-grade gene on 30 Genomics England panels |

**Commonly reported features of Lynch syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Weight loss — Very frequent (99-80%)
- Constipation — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Gastrointestinal hemorrhage — Very frequent (99-80%)
- Neoplasm of the skin — Very frequent (99-80%)
- Adenoma sebaceum — Very frequent (99-80%)
- Glioblastoma multiforme — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015792/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MSH6](https://sugi.bio/atlas/gene/MSH6/) |
| Protein change (HGVS p.) | p.Glu645fs |
| Coding change (HGVS c.) | c.1933del |
| MANE Select transcript | [NM_000179](https://www.ncbi.nlm.nih.gov/nuccore/NM_000179) |
| dbSNP | [rs1558663559](https://www.ncbi.nlm.nih.gov/snp/rs1558663559/) |
| Variant type | Deletion |
| Location | chr2:47799914-47799914 (GRCh38) |
| ClinVar | [VCV633316](https://www.ncbi.nlm.nih.gov/clinvar/variation/633316/) |

**All HGVS expressions:** `LRG_219:g.21770del`, `NC_000002.11:g.48027055del`, `NC_000002.12:g.47799916del`, `NG_007111.1:g.21770del`, `NM_000179.2:c.1933del`, `NM_000179.2:c.1933delG`, `NM_000179.3:c.1933del`, `NM_001281492.2:c.1543del`, `NM_001281493.2:c.1027del`, `NM_001281494.2:c.1027del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.424, GERP 1.36, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MSH6** population constraint: LOEUF 0.841, pLI 7.9694e-20, missense-Z -3.8555; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mismatch repair cancer syndrome 1** — Definitive (AR)
- **Lynch syndrome** — Definitive (AD)
- **hereditary breast carcinoma** — Disputed (AD)

## Protein context {#protein}

Residue **645** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 77.93, 46% of residues very-high.

**8 experimental structure(s)** (PDB): [2GFU](https://www.rcsb.org/structure/2GFU), [2O8B](https://www.rcsb.org/structure/2O8B), [2O8C](https://www.rcsb.org/structure/2O8C), [2O8D](https://www.rcsb.org/structure/2O8D), [2O8E](https://www.rcsb.org/structure/2O8E), [2O8F](https://www.rcsb.org/structure/2O8F).

## What this gene does {#gene-function}

*Describes the biological roles of MSH6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MSH6's established molecular role includes ATP-dependent activity, acting on DNA. In Reactome, MSH6 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MSH2**, **Defective Mismatch Repair Associated With MSH6**.

**Disease mechanism (Reactome):** MSH6 loss or alteration is curated in [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928), [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968).

### Pathways affected {#pathways}

MSH6 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928) | curated |
| ⚕ [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968) | curated |
| [Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)](https://reactome.org/content/detail/R-HSA-5358565) | curated |
| [Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)](https://reactome.org/content/detail/R-HSA-9968295) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ATP-dependent activity, acting on DNA, enzyme binding, mismatched DNA binding, histone H3K36me3 reader activity.

**Biological process:** DNA repair, mismatch repair, negative regulation of DNA recombination.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-09.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic, 1 likely pathogenic).

**Submission history:** 4 submissions (2018–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-03-14 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-16 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-07 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-09 |

## Associated conditions {#conditions}

[Lynch syndrome 5](https://sugi.bio/atlas/disease/lynch-syndrome-5/), [endometrial carcinoma](https://sugi.bio/atlas/disease/endometrial-carcinoma/), [Lynch syndrome](https://sugi.bio/atlas/disease/lynch-syndrome/).

**Reported phenotype names (ClinVar):** Lynch syndrome 5, Endometrial carcinoma, Lynch syndrome, not provided, Hereditary non-polyposis colorectal cancer, type 5, Colorectal cancer, hereditary nonpolyposis, type 5, Endometrial carcinoma, somatic, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Same-residue context {#hotspot}

Residue **645** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MSH6 p.Glu645Ter](/variant/msh6-p-glu645ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH6 variant pages (same residue, condition, or type): [MSH6 p.Glu645Ter](/variant/msh6-p-glu645ter), [MSH6 p.Glu645=](/variant/msh6-p-glu645), [MSH6 c.3173-1_3173del](/variant/msh6-c-3173-minus-1-3173del), [MSH6 c.3173-433_3556+228del](/variant/msh6-c-3173-minus-433-3556-plus-228del), [MSH6 c.3379_3438+5del](/variant/msh6-c-3379-3438-plus-5del), [MSH6 c.3646_3646+3del](/variant/msh6-c-3646-3646-plus-3del), [MSH6 c.3647-6_3647-1del](/variant/msh6-c-3647-minus-6-3647-minus-1del), [MSH6 c.3798_3801+26del](/variant/msh6-c-3798-3801-plus-26del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 633316). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*