Classification rationale

Unclassified

No rationale recorded.

Gene diagram · NM_024675.3 · variants mapped to exon structure

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 0 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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.10151e-06; MAF= 0.00031%, 5/1612120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24356e-06; MAF= 0.00042%, 5/1178256 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97741e-06; MAF= 0.00040%, 1/251420 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79306e-06; MAF= 0.00088%, 1/113726 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,612,120
0 hom · FAF 0.00012%

European (non-Finnish)

5 / 1,178,256

0.00042%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,420
0 hom

European (non-Finnish)

1 / 113,726

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 128144)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV104552896, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

18053174 ↗ Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. ONCOKB

25529982 ↗ A novel PALB2 truncating mutation in an Italian family with male breast cancer. ONCOKB

28279176 ↗ PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. ONCOKB

28779002 ↗ Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. ONCOKB

28858227 ↗ The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. ONCOKB

29484706 ↗ 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. ONCOKB

17200671 ↗ Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. CLINVAR

19264984 ↗ Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR