# NM_000249.4(MLH1):c.1731G>T (p.Ser577=)

https://sugi.bio/variant/mlh1-p-ser577

## Summary

**MLH1 p.Ser577= (c.1731G>T)** is classified **Pathogenic/Likely pathogenic** in MLH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-09). No allele count reported in gnomAD v4.1 (AN 1,595,716); Associated with Hereditary nonpolyposis colorectal neoplasms.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs63751657 · 3 submitters · 3 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,595,716)

## For patients & families {#patients}

This is a change in the MLH1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Hereditary nonpolyposis colorectal neoplasms.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MLH1](https://sugi.bio/atlas/gene/MLH1/) |
| Protein change (HGVS p.) | p.Ser577= |
| Coding change (HGVS c.) | c.1731G>T |
| MANE Select transcript | [NM_000249](https://www.ncbi.nlm.nih.gov/nuccore/NM_000249) |
| dbSNP | [rs63751657](https://www.ncbi.nlm.nih.gov/snp/rs63751657/) |
| Variant type | single nucleotide variant |
| Location | chr3:37042331-37042331 (GRCh38) |
| ClinVar | [VCV525656](https://www.ncbi.nlm.nih.gov/clinvar/variation/525656/) |

**All HGVS expressions:** `LRG_216:g.53982G>T`, `LRG_216t1:c.1731G>T`, `NC_000003.11:g.37083822G>T`, `NC_000003.12:g.37042331G>T`, `NG_007109.2:g.53982G>T`, `NM_000249.4:c.1731G>T`, `NM_001167617.3:c.1437G>T`, `NM_001167618.3:c.1008G>T`, `NM_001167619.3:c.1008G>T`, `NM_001258271.2:c.1731G>T`, `NM_001258273.2:c.1008G>T`, `NM_001258274.3:c.1008G>T`, `NM_001354615.2:c.1008G>T`, `NM_001354616.2:c.1008G>T`, `NM_001354617.2:c.1008G>T`, `NM_001354618.2:c.1008G>T`, `NM_001354619.2:c.1008G>T`, `NM_001354620.2:c.1437G>T`, `NM_001354621.2:c.708G>T`, `NM_001354622.2:c.708G>T`, `NM_001354623.2:c.708G>T`, `NM_001354624.2:c.657G>T`, `NM_001354625.2:c.657G>T`, `NM_001354626.2:c.657G>T`, `NM_001354627.2:c.657G>T`, `NM_001354628.2:c.1731G>T`, `NM_001354629.2:c.1632G>T`, `NM_001354630.2:c.1731G>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.64) — consistent with the pathogenic call
- Conservation: phyloP 8.671, GERP 1.48, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.02**, donor loss **0.64**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.64**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.66** (loss), gain 0.00 / loss 0.66. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,595,716)** — 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}

**MLH1** population constraint: LOEUF 0.639, pLI 0.00086326, missense-Z 1.0943; 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):

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

## Protein context {#protein}

Residue **577** lies in a β-strand; the 'interaction with exo1' region.

AlphaFold model confidence (whole protein): pLDDT 77.89, 51% of residues very-high.

**13 experimental structure(s)** (PDB): [3RBN](https://www.rcsb.org/structure/3RBN), [4P7A](https://www.rcsb.org/structure/4P7A), [5U5P](https://www.rcsb.org/structure/5U5P), [6WBA](https://www.rcsb.org/structure/6WBA), [6WBB](https://www.rcsb.org/structure/6WBB), [6WBC](https://www.rcsb.org/structure/6WBC).

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

*Describes the biological roles of MLH1 (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:** MLH1's established molecular role includes chromatin binding. p.Ser577= falls in the interaction with exo1 region. In Reactome, MLH1 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MLH1**, **Defective Mismatch Repair Associated With PMS2**.

**Disease mechanism (Reactome):** MLH1 loss or alteration is curated in [Defective Mismatch Repair Associated With MLH1](https://reactome.org/content/detail/R-HSA-5545483), [Defective Mismatch Repair Associated With PMS2](https://reactome.org/content/detail/R-HSA-5632987).

### Pathways affected {#pathways}

MLH1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Mismatch Repair Associated With MLH1](https://reactome.org/content/detail/R-HSA-5545483) | curated |
| ⚕ [Defective Mismatch Repair Associated With PMS2](https://reactome.org/content/detail/R-HSA-5632987) | 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 |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |
| [Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)](https://reactome.org/content/detail/R-HSA-5358606) | electronic |

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

**Molecular function:** chromatin binding, enzyme activator activity, enzyme binding.

**Biological process:** meiotic mismatch repair, mismatch repair.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-06-09.

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

**Submission history:** 3 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-09 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-06-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-11 |

## Associated conditions {#conditions}

[Hereditary nonpolyposis colorectal neoplasms](https://sugi.bio/atlas/disease/hereditary-nonpolyposis-colorectal-neoplasms/), [Lynch syndrome 2](https://sugi.bio/atlas/disease/lynch-syndrome-2/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary nonpolyposis colorectal neoplasms, Hereditary cancer-predisposing syndrome, Colorectal cancer, hereditary nonpolyposis, type 2, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Lynch syndrome 2, MLH1-Related Lynch Syndrome, COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2.

## Same-residue context {#hotspot}

Residue **577** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MLH1 p.Ser577Ter](/variant/mlh1-p-ser577ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MLH1 variant pages (same residue, condition, or type): [MLH1 p.Ser577Ter](/variant/mlh1-p-ser577ter), [MLH1 p.Ser577Trp](/variant/mlh1-p-ser577trp), [MLH1 p.Ser577Leu](/variant/mlh1-p-ser577leu), [MLH1 p.Ser577Pro](/variant/mlh1-p-ser577pro), [MLH1 c.1038+1G>C](/variant/mlh1-c-1038-plus-1g-c), [MLH1 c.1039-1G>A](/variant/mlh1-c-1039-minus-1g-a), [MLH1 c.1039-2A>G](/variant/mlh1-c-1039-minus-2a-g), [MLH1 c.1039-2A>T](/variant/mlh1-c-1039-minus-2a-t).

### 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 525656). 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.*