# NM_024675.4(PALB2):c.1419A>C (p.Pro473=)

https://sugi.bio/variant/palb2-p-pro473

## Summary

**PALB2 p.Pro473= (c.1419A>C)** is classified **Benign/Likely benign** in PALB2 (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.09%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs62625275 · 23 submitters · 5 linked conditions · low-frequency (popmax 1.09%, afr)

## For patients & families {#patients}

This is a change in the PALB2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 23 submitters, and is linked to breast-ovarian cancer, familial, susceptibility to, 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.*

**Support & next steps:** [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.Pro473= |
| Coding change (HGVS c.) | c.1419A>C |
| MANE Select transcript | [NM_024675](https://www.ncbi.nlm.nih.gov/nuccore/NM_024675) |
| dbSNP | [rs62625275](https://www.ncbi.nlm.nih.gov/snp/rs62625275/) |
| Variant type | single nucleotide variant |
| Location | chr16:23635127-23635127 (GRCh38) |
| ClinVar | [VCV126601](https://www.ncbi.nlm.nih.gov/clinvar/variation/126601/) |

**All HGVS expressions:** `LRG_308:g.11231A>C`, `LRG_308t1:c.1419A>C`, `NC_000016.10:g.23635127T>G`, `NC_000016.9:g.23646448T>G`, `NG_007406.1:g.11231A>C`, `NM_024675.4:c.1419A>C`

## 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 -0.141, GERP -0.665 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.407**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.09%** (afr) · FAF95 1.03% · FAF99 1.01% · 821/75,062 in the highest group · 956/1,614,242 alleles overall — low-frequency (popmax 1.09%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.09% | 91 |
| Middle Eastern | 0.165% | 606 |
| Remaining individuals (not grpmax-eligible) | 0.0864% | 1,158 |
| Admixed American | 0.0733% | 1,364 |
| South Asian | 0.00439% | 22,772 |
| European (non-Finnish) | 0.00195% | 51,306 |

*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 **473** lies in the 'disordered' region; a UniProt-annotated variant site (risk factor for brovca5); the 'dna-binding (with the preference d loop > dsdna > ssdna)' 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.Pro473= falls in the disordered 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (14 Benign, 9 Likely benign).

**Submission history:** 23 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-01-21 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2016-07-11 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-16 |
| True Health Diagnostics | Likely benign | no assertion criteria provided | clinical testing | 2018-06-18 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing | 2017-06-20 |
| Leiden Open Variation Database | Benign | no assertion criteria provided | curation | 2019-05-13 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | Benign | no assertion criteria provided | clinical testing |  |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2015-04-13 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Benign | criteria provided, single submitter | clinical testing | 2022-12-19 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-06-18 |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2015-12-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-12-16 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2023-04-03 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Benign | criteria provided, single submitter | clinical testing | 2025-03-04 |

## Associated conditions {#conditions}

[breast-ovarian cancer, familial, susceptibility to, 5](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-5/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Breast-ovarian cancer, familial, susceptibility to, 5, Familial cancer of breast, Hereditary cancer-predisposing syndrome, not specified, not provided, Malignant tumor of breast, Hereditary breast ovarian cancer syndrome, Breast and/or ovarian cancer, Hereditary neoplastic syndrome, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **473** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PALB2 p.Pro473fs](/variant/palb2-p-pro473fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PALB2 variant pages (same residue, condition, or type): [PALB2 p.Pro473Ala](/variant/palb2-p-pro473ala), [PALB2 p.Pro473Ser](/variant/palb2-p-pro473ser), [PALB2 p.Pro473Arg](/variant/palb2-p-pro473arg), [PALB2 p.Pro473Leu](/variant/palb2-p-pro473leu), [PALB2 p.Pro473fs](/variant/palb2-p-pro473fs), [PALB2 c.3350+4A>G](/variant/palb2-c-3350-plus-4a-g), [PALB2 p.Arg1117Lys](/variant/palb2-p-arg1117lys), [PALB2 p.Gln228Ter](/variant/palb2-p-gln228ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 126601). 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.*