# NM_024675.4(PALB2):c.661_662delinsTA (p.Val221Ter)

https://sugi.bio/variant/palb2-p-val221ter

## Summary

**PALB2 p.Val221Ter (c.661_662delinsTA)** is classified **Pathogenic** in PALB2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-08-16). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs587782531 · 9 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PALB2 gene that is considered disease-causing, submitted by 9 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Val221Ter |
| Coding change (HGVS c.) | c.661_662delinsTA |
| MANE Select transcript | [NM_024675](https://www.ncbi.nlm.nih.gov/nuccore/NM_024675) |
| dbSNP | [rs587782531](https://www.ncbi.nlm.nih.gov/snp/rs587782531/) |
| Variant type | Indel |
| Location | chr16:23635884-23635885 (GRCh38) |
| ClinVar | [VCV142540](https://www.ncbi.nlm.nih.gov/clinvar/variation/142540/) |

**All HGVS expressions:** `LRG_308:g.10473_10474delinsTA`, `NC_000016.10:g.23635884_23635885delinsTA`, `NC_000016.9:g.23647205_23647206delinsTA`, `NG_007406.1:g.10473_10474delinsTA`, `NM_024675.3:c.661_662delGTinsTA`, `NM_024675.4:c.661_662delinsTA`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.381, GERP -3.31 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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 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 indel 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 **221** lies in the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region.

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. p.Val221Ter falls in the dna-binding (with the preference d loop > dsdna > ssdna) region. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-08-16.

**Submitter consensus:** unanimous (9/9 Pathogenic).

**Submission history:** 9 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Leiden Open Variation Database | Pathogenic | no assertion criteria provided | curation | 2019-05-13 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-08 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-24 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-04-04 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-06 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-16 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-08-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, Familial cancer of breast, Malignant tumor of breast, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, none provided, BREAST CANCER, FAMILIAL.

## Same-residue context {#hotspot}

Residue **221** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PALB2 p.Val221fs](/variant/palb2-p-val221fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PALB2 variant pages (same residue, condition, or type): [PALB2 p.Val221=](/variant/palb2-p-val221), [PALB2 p.Val221fs](/variant/palb2-p-val221fs), [PALB2 p.Val221Ala](/variant/palb2-p-val221ala), [PALB2 p.Val221Ile](/variant/palb2-p-val221ile), [PALB2 p.Ala842fs](/variant/palb2-p-ala842fs), [PALB2 c.2223_2224delinsG](/variant/palb2-c-2223-2224delinsg), [PALB2 c.2586+1_2586+2delinsTA](/variant/palb2-c-2586-plus-1-2586-plus-2delinsta), [PALB2 c.3249_3253delinsAGCC](/variant/palb2-c-3249-3253delinsagcc).

### 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 142540). 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.*