NM_024675.4:c.509_510delGA (p.Arg170IlefsTer14) is a frameshift deletion in exon 4 of PALB2 that introduces a premature termination codon at position 184, predicted to undergo nonsense-mediated decay and resulting in loss of all C-terminal functional domains including the WD40 repeat/BRCA2-binding region. Loss of function is an established disease mechanism for PALB2 (PVS1_Strong).1 The variant is significantly enriched in breast cancer cases compared to population controls. Noskowicz et al. (2014) identified the variant in 10/3,924 (0.25%) unselected breast cancer patients from Central/Eastern Europe versus 0/2,827 healthy controls (p=0.007). Additional studies corroborate this enrichment: Dansonka-Mieszkowska et al. (2010) found the variant in 6/987 (0.6%) cancer cases versus 1/1,310 controls; Kluska et al. (2017) detected it in 0.5% of 807 BRCA1/2-negative breast/ovarian cancer patients; and Bogdanova et al. (2011) identified it in 2/203 bilateral breast cancer patients. Collectively, these studies meet PS4 at Strong strength.2 The premature termination codon at position 184 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, consistent with loss of critical functional domains. Under the PALB2 VCEP, this satisfies PM5_Supporting. The variant is present at low frequency in gnomAD (v4.1: 30/1,614,006, 0.00186%; v2.1: 9/251,446, 0.00358%), with no homozygotes. This frequency exceeds the PALB2 VCEP PM2_Supporting threshold (≤0.000333%) and remains well below benign population thresholds (BA1 >0.1%, BS1 >0.01%), providing neither pathogenic nor benign population evidence.3 SpliceAI predicts no cryptic splice effect (max delta = 0.00). No co-segregation or non-segregation data are available. No functional studies specific to this variant have been published.4
PALB2
Final classification
Pathogenic
PALB2 c.509_510del · p.Arg170IlefsTer14
PALB2
NM_024675.4:c.509_510delGA (p.Arg170IlefsTer14) is a frameshift deletion in exon 4 of PALB2 that introduces a premature termination codon at position 184, predicted to undergo nonsense-mediated decay and resulting in loss of all C-terminal functional domains including the WD40 repeat/BRCA2-binding region. Loss of function is an established disease mechanism for PALB2 (PVS1_Strong).
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule5 (Pathogenic.Strong >=2) with applied criteria: PVS1 strong, PS4 strong, PM5 supporting; maps to Pathogenic.
Classification rationale
PVS1PS4PM5
Pathogenic
PALB2 c.509_510del
PVS1 + PS4 + PM5
→
Pathogenic
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
30 / 1,614,006
0.0019%
Highest · European (non-Finnish)
0.0025%
Homozygotes
0
grpmax FAF
0.0017%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 29 / 1,180,016 | 0.0025% | 0 |
| Admixed American | 0 / 59,980 | — | — |
| European (Finnish) | 0 / 64,024 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,892 | — | — |
| Middle Eastern | 0 / 6,084 | — | — |
| South Asian | 0 / 91,088 | — | — |
| Ashkenazi Jewish | 0 / 29,606 | — | — |
| African/African American | 0 / 74,916 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 1.85873e-05; MAF= 0.00186%, 30/1614006 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.45759e-05; MAF= 0.00246%, 29/1180016 alleles, homozygotes = 0); grpmax FAF= 1.724e-05.
Overall AF
9 / 251,446
0.0036%
Highest · Remaining individuals
0.016%
Homozygotes
0
grpmax FAF
0.0034%
Allele frequency by ancestry — gnomAD v2.1
observed in 2 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Remaining individuals | 1 / 6,138 | 0.016% | 0 |
| European (non-Finnish) | 8 / 113,732 | 0.007% | 0 |
| African/African American | 0 / 16,256 | — | — |
| Admixed American | 0 / 34,588 | — | — |
| Ashkenazi Jewish | 0 / 10,080 | — | — |
| East Asian | 0 / 18,394 | — | — |
| European (Finnish) | 0 / 21,646 | — | — |
| South Asian | 0 / 30,612 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 3.5793e-05; MAF= 0.00358%, 9/251446 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00016292; MAF= 0.01629%, 1/6138 alleles, homozygotes = 0); grpmax FAF= 3.419e-05.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Pathogenic (49 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 126757)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108015612, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 56 PMIDs triaged · 8 high-priority
56papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
28279176 ↗
functional
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
The PALB2 gene encodes a protein that plays a crucial role in maintaining genomic integrity. Germline inactivating mutations in PALB2 are associated with an increased risk of breast and ovarian cancer. The prevalence and spectrum of recurrent PALB2 germline mutations in breast and ovarian cancer patients from Poland is not clearly defined. PALB2 exons were amplified from 460 BRCA1/2-mutation negat
BS3PM1PS3
18053174 ↗
functional
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. We screened all coding exons of PALB2 in a sample of 50
BS3PM1PS3
25529982 ↗
functional
A novel PALB2 truncating mutation in an Italian family with male breast cancer.
Male breast cancer (MBC) is a rare disease, accounting for ~1% of all breast cancer cases worldwide. Although other genes are also involved, predisposing genetic factors to MBC include germline mutations in the BRCA genes (BRCA2). Among the other genes, partner and localizer of BRCA2 (PALB2) is considered a moderate-penetrance breast cancer susceptibility gene that may also play a role in MBC pred
BS3PM1PS3
28279176 ↗
functional
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
The PALB2 gene encodes a protein that plays a crucial role in maintaining genomic integrity. Germline inactivating mutations in PALB2 are associated with an increased risk of breast and ovarian cancer. The prevalence and spectrum of recurrent PALB2 germline mutations in breast and ovarian cancer patients from Poland is not clearly defined. PALB2 exons were amplified from 460 BRCA1/2-mutation negat
BS3PS3PS4
28779002 ↗
functional
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. Gene coding regions were enriched via PCR, s
BS3PM1PS3
28858227 ↗
functional
The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. Since its identification as a BRCA2
BS3PM1PS3
29484706 ↗
functional
Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes.
Breast cancer (BC) is the most common neoplasm in women, with 5%-10% patients showing a familial predisposition, where germline mutations in BRCA1/BRCA2 genes are found in -20% of cases. Next-generation sequencing (NGS) is among the best available options for genetic screening, providing several benefits that include enhanced sensitivity and unbiased mutation detection. PALB2 (partner and localize
BS3PM1PS3
17200671 ↗
functional
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.
PALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutations cause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenic mutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia,
BS3PP5PS3PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links