# NM_024675.4(PALB2):c.1818T>C (p.Phe606=)

https://sugi.bio/variant/palb2-p-phe606

## Summary

**PALB2 p.Phe606= (c.1818T>C)** is classified **Benign/Likely benign** in PALB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-25). Very rare (popmax 0.00133%, afr); Associated with hereditary breast carcinoma.

**At a glance:** Benign/Likely benign · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 0.00133%, 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 2 submitters, 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.Phe606= |
| Coding change (HGVS c.) | c.1818T>C |
| MANE Select transcript | [NM_024675](https://www.ncbi.nlm.nih.gov/nuccore/NM_024675) |
| Variant type | single nucleotide variant |
| Location | chr16:23630336-23630336 (GRCh38) |
| ClinVar | [VCV3903607](https://www.ncbi.nlm.nih.gov/clinvar/variation/3903607/) |

**All HGVS expressions:** `LRG_308:g.16022T>C`, `LRG_308t1:c.1818T>C`, `NC_000016.10:g.23630336A>G`, `NC_000016.9:g.23641657A>G`, `NG_007406.1:g.16022T>C`, `NM_001407296.1:c.1758T>C`, `NM_001407297.1:c.1818T>C`, `NM_001407298.1:c.1818T>C`, `NM_001407299.1:c.1818T>C`, `NM_001407300.1:c.1818T>C`, `NM_001407301.1:c.1818T>C`, `NM_001407302.1:c.1818T>C`, `NM_001407304.1:c.933T>C`, `NM_001407305.1:c.933T>C`, `NM_001407306.1:c.933T>C`, `NM_001407307.1:c.933T>C`, `NM_001407308.1:c.933T>C`, `NM_001407309.1:c.933T>C`, `NM_001407310.1:c.933T>C`, `NM_001407311.1:c.933T>C`, `NM_001407312.1:c.30T>C`, `NM_001407313.1:c.30T>C`, `NM_001407314.1:c.49-1061T>C`, `NM_024675.4:c.1818T>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 1.518, GERP -3.58, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 2.378**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.23 acceptor 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 **0.00133%** (afr) · 1/74,930 in the highest group · 1/1,614,090 alleles overall — very rare (popmax 0.00133%, afr).

*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 **606** lies in a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); an α-helix.

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-25.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-01-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-25 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **606** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PALB2 p.Phe606fs](/variant/palb2-p-phe606fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PALB2 variant pages (same residue, condition, or type): [PALB2 p.Phe606fs](/variant/palb2-p-phe606fs), [PALB2 p.Phe606Leu](/variant/palb2-p-phe606leu), [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), [PALB2 p.Gln692Ter](/variant/palb2-p-gln692ter), [PALB2 p.Glu3Ter](/variant/palb2-p-glu3ter), [PALB2 p.Gly853=](/variant/palb2-p-gly853).

### 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 3903607). 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.*