# NM_024675.4(PALB2):c.1933del (p.Glu645fs)

https://sugi.bio/variant/palb2-p-glu645fs

## Summary

**PALB2 p.Glu645fs (c.1933del)** is classified **Likely pathogenic** in PALB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-07-21). No gnomAD frequency available for this variant; Associated with hereditary breast carcinoma.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1567218463 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PALB2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hereditary breast carcinoma.

*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, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PALB2 is a diagnostic-grade gene on 23 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017142/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PALB2](https://sugi.bio/atlas/gene/PALB2/) |
| Protein change (HGVS p.) | p.Glu645fs |
| Coding change (HGVS c.) | c.1933del |
| MANE Select transcript | [NM_024675](https://www.ncbi.nlm.nih.gov/nuccore/NM_024675) |
| dbSNP | [rs1567218463](https://www.ncbi.nlm.nih.gov/snp/rs1567218463/) |
| Variant type | Deletion |
| Location | chr16:23630221-23630221 (GRCh38) |
| ClinVar | [VCV2574090](https://www.ncbi.nlm.nih.gov/clinvar/variation/2574090/) |

**All HGVS expressions:** `LRG_308:g.16137del`, `LRG_308t1:c.1933del`, `NC_000016.10:g.23630221del`, `NC_000016.9:g.23641542del`, `NG_007406.1:g.16137del`, `NM_001407296.1:c.1873del`, `NM_001407297.1:c.1933del`, `NM_001407298.1:c.1933del`, `NM_001407299.1:c.1933del`, `NM_001407300.1:c.1933del`, `NM_001407301.1:c.1933del`, `NM_001407302.1:c.1933del`, `NM_001407304.1:c.1048del`, `NM_001407305.1:c.1048del`, `NM_001407306.1:c.1048del`, `NM_001407307.1:c.1048del`, `NM_001407308.1:c.1048del`, `NM_001407309.1:c.1048del`, `NM_001407310.1:c.1048del`, `NM_001407311.1:c.1048del`, `NM_001407312.1:c.145del`, `NM_001407313.1:c.145del`, `NM_001407314.1:c.49-946del`, `NM_024675.4:c.1933del`

## 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 2.832, GERP -0.428, phastCons 0.223 — 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 5 of 13**, 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}

**PALB2** population constraint: LOEUF 0.9, pLI 1.2379e-19, missense-Z 0.8204; 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):

- **Fanconi anemia complementation group N** — Definitive (AR)
- **PALB2-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **645** lies in a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5).

AlphaFold model confidence (whole protein): pLDDT 54.07, 23% of residues very-high.

**4 experimental structure(s)** (PDB): [2W18](https://www.rcsb.org/structure/2W18), [3EU7](https://www.rcsb.org/structure/3EU7), [7S4A](https://www.rcsb.org/structure/7S4A), [8YAP](https://www.rcsb.org/structure/8YAP).

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

*Describes the biological roles of PALB2 (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:** PALB2's established molecular role includes DNA binding. In Reactome, PALB2 is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** PALB2 loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

PALB2 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |

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

**Molecular function:** DNA binding.

**Biological process:** double-strand break repair via homologous recombination.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-07-21.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| deCODE genetics, Amgen | Likely pathogenic | no assertion criteria provided | research | 2023-07-21 |

## Associated conditions {#conditions}

[hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Familial cancer of breast, hereditary breast carcinoma, Hereditary breast cancer, BREAST CANCER, FAMILIAL.

## Similar variants {#similar}

Related PALB2 variant pages (same residue, condition, or type): [PALB2 p.Glu645=](/variant/palb2-p-glu645), [PALB2 p.Glu178fs](/variant/palb2-p-glu178fs), [PALB2 p.Gly1121fs](/variant/palb2-p-gly1121fs), [PALB2 p.Leu531fs](/variant/palb2-p-leu531fs), [PALB2 p.Ser172fs](/variant/palb2-p-ser172fs), [PALB2 p.Phe1181fs](/variant/palb2-p-phe1181fs), [PALB2 c.1686del](/variant/palb2-c-1686del), [PALB2 c.2515-17_2522del](/variant/palb2-c-2515-minus-17-2522del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2574090). 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.*