# NM_000535.7(PMS2):c.2005A>T (p.Ser669Cys)

https://sugi.bio/variant/pms2-p-ser669cys

## Summary

**PMS2 p.Ser669Cys (c.2005A>T)** is classified **Uncertain significance** in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-19). AlphaMissense: likely benign (0.0959); Very rare (popmax 8.54e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1554297049 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.54e-05%, nfe)

## For patients & families {#patients}

This is a change in the PMS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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 | [PMS2](https://sugi.bio/atlas/gene/PMS2/) |
| Protein change (HGVS p.) | p.Ser669Cys |
| Coding change (HGVS c.) | c.2005A>T |
| MANE Select transcript | [NM_000535](https://www.ncbi.nlm.nih.gov/nuccore/NM_000535) |
| dbSNP | [rs1554297049](https://www.ncbi.nlm.nih.gov/snp/rs1554297049/) |
| Variant type | single nucleotide variant |
| Location | chr7:5986760-5986760 (GRCh38) |
| ClinVar | [VCV486045](https://www.ncbi.nlm.nih.gov/clinvar/variation/486045/) |

**All HGVS expressions:** `LRG_161:g.27347A>T`, `LRG_161t1:c.2005A>T`, `NC_000007.13:g.6026391T>A`, `NC_000007.14:g.5986760T>A`, `NG_008466.1:g.27347A>T`, `NM_000535.7:c.2005A>T`, `NM_001322003.2:c.1600A>T`, `NM_001322004.2:c.1600A>T`, `NM_001322005.2:c.1600A>T`, `NM_001322006.2:c.1849A>T`, `NM_001322007.2:c.1687A>T`, `NM_001322008.2:c.1687A>T`, `NM_001322009.2:c.1600A>T`, `NM_001322010.2:c.1444A>T`, `NM_001322011.2:c.1072A>T`, `NM_001322012.2:c.1072A>T`, `NM_001322013.2:c.1432A>T`, `NM_001322014.2:c.2005A>T`, `NM_001322015.2:c.1696A>T`, `NR_136154.1:n.2092A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0959)
- REVEL 0.225 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.356 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.92, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.40** across the covering region of the MANE Select transcript (5,973,402–5,986,797), spanning 13,395 bp. Chi-square p 2e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.36 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.54e-05%** (nfe) · 1/1,170,944 in the highest group · 1/1,587,186 alleles overall — very rare (popmax 8.54e-05%, nfe).

*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}

**PMS2** population constraint: LOEUF 0.898, pLI 5.3905e-09, missense-Z 0.36886; 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)
- **hereditary breast carcinoma** — Disputed (AD)
- **mismatch repair cancer syndrome 1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.37, 36% of residues very-high.

**9 experimental structure(s)** (PDB): [1EA6](https://www.rcsb.org/structure/1EA6), [1H7S](https://www.rcsb.org/structure/1H7S), [1H7U](https://www.rcsb.org/structure/1H7U), [5U5R](https://www.rcsb.org/structure/5U5R), [6MFQ](https://www.rcsb.org/structure/6MFQ), [7RCB](https://www.rcsb.org/structure/7RCB) — incl. mutant structure 6MFQ.

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

*Describes the biological roles of PMS2 (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:** PMS2's established molecular role includes DNA binding. In Reactome, PMS2 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MLH1**, **Defective Mismatch Repair Associated With PMS2**.

**Disease mechanism (Reactome):** PMS2 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}

PMS2 participates in **6 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 |
| [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:** DNA binding, single base insertion or deletion binding.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-19.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-05-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-19 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-30 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary nonpolyposis colorectal neoplasms, Hereditary cancer-predisposing syndrome, not provided, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, none provided.

## Same-residue context {#hotspot}

Residue **669** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PMS2 p.Ser669fs](/variant/pms2-p-ser669fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PMS2 variant pages (same residue, condition, or type): [PMS2 p.Ser669Asn](/variant/pms2-p-ser669asn), [PMS2 p.Ser669Arg](/variant/pms2-p-ser669arg), [PMS2 p.Ser669Gly](/variant/pms2-p-ser669gly), [PMS2 p.Ser669Ile](/variant/pms2-p-ser669ile), [PMS2 p.Ser669Thr](/variant/pms2-p-ser669thr), [PMS2 p.Ser669=](/variant/pms2-p-ser669), [PMS2 p.Ser669fs](/variant/pms2-p-ser669fs), [PMS2 c.163+2T>C](/variant/pms2-c-163-plus-2t-c).

### 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 486045). 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.*