Inheritance

Autosomal dominant

Prevalence

 1:70 (common)

Source: Orphanet Orpha:145

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Breast/Ovarian Cancer GCEP, accessed 06.27.2027

Clinical Validity Scoring Notes and points

Not provided

Source: ClinGen Breast/Ovarian Cancer GCEP, accessed 06.27.2027

Clinical Validity Points Total

18

Source: ClinGen Breast/Ovarian Cancer GCEP, accessed 06.27.2027

Clinical Validity Classification

Definitive

Source: ClinGen Breast/Ovarian Cancer GCEP, accessed 06.27.2027

Molecular Mechanism

Loss of function

Summary:

• >10 truncating, NMD+ variants identified in individuals with early onset and/or familial breast cancer, statistical increase compared to controls (PMIDs: 17200668, 24136930).

• Increased risk of breast cancer observed in individuals who harbor truncating, splice, or deletion variants with a cumulative risk of 14% by 70 years of age. (PMID:25099575)

• LOF is also the mechanism for autosomal recessive Fanconi anemia.

Detailed Lit review notes:

• PMID: 17200668 - Statistical increase in truncating variants in PALB2 in individuals with familial breast cancer (1.1%, 1/923) compared with controls (0%), p=-0.0004. All cases had BRCA1 and BRCA2 excluded. Controls were healthy individuals. 7 of the variants reported in table 1 are expected to undergo NMD: c.2386G>T p.G796* (NMD+), 2982insT, A995fs (NMD+), 3113G → A W1038X(NMD+), 3113G → A W1038X (NMD+), 3116delA Asn1039Ilefs*2 (NMD+), 3116delA N1039fs(NMD+), 3116delA N1039fs(NMD+). The 3549C → G Y1183X variant, reported in 3 individuals is not expected to undergo NMD.

• PMID: 24136930 - PALB2 sequenced in 409 breast / ovarian cancer patients negative for BRCA1/2. 10 truncations and three large genomic rearrangements identified in the patient cohort, one identified in 1226 controls (3.9% vs 0.08%, P=2.6x10-9). Table 2 shows clinical details and the variants identified, many truncations listed in individuals with early onset breast cancer and/or family history. Highlighted for curation: [1] c.73A>T p.K25*, exon 1 in individual with bil. BrCa at 75y, family history of BrCa in daughter age 40 [2] c.172_175del Gln60Argfs*7, exon 3, found in 4 individuals with BrCa onset at 34, 39, 38, and 42/52 all with a family history [3]c.509_510delGA p.(Arg170Ilefs*14) exon 4, BrCa at 59 w/ family history in several individuals including sister at 40y [4] c.661_662delinsTA p.V221*, exon 4, BrCa at 46, family history in several individuals including sister at 50. Segregations shown in fig 3, counted 3 segregations across the 5 families.

• 25099575 - Risk of breast cancer among 362 members of 154 families who had truncating, splice or deletion in PALB2. Age specific breast cancer risk compared with the general population was 8-9x as high among those <40years, 6-8x as high for 40-60 year olds, and 5x high among those >60y. Estimated cumulative risk among female mutation carriers was 14% by 70 years.

Penetrance

(list source/PMID)

Reduced

Absolute risk 41-60%, NCCN Guidelines v3

Age of Onset

(list source/PMID)

Adulthood

Severity

Moderate

Clinical Features

Early onset breast cancer (≤50 y years)

Triple negative breast cancer

Multiple primary breast cancer

Male breast cancer

Family history of breast and/or ovarian cancer (2 or more affected 1st or second degree relatives)

Ovarian cancer

Sources: NCCN Guidelines v3

Gene SOPs & Notes

No ClinGen VCEP guidelines published. Reviewed truncations in ClinVar, no red flags

Curation Summary:

The PALB2 gene is associated with autosomal dominant hereditary breast and ovarian cancer, which is characterized by increased risk of both male and female breast cancer, and ovarian cancer (PMID: 17200668, 24136930, 25099575, 26720728, 30733081). The National Comprehensive Cancer Network provides recommended screening management and risk information for individuals with a heterozygous pathogenic variant identified in this gene (https://www.nccn.org ). PALB2 is also associated with autosomal recessive Fanconi anemia (PMID: 17200671, 17200672). Fanconi anemia is characterized by bone marrow failure, cancer susceptibility including acute myeloid leukemia and solid tumors, developmental delay and/or intellectual disability, and physical features including short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, ophthalmic features, and genitourinary tract anomalies. 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06.28.2023 https://broadinstitute.atlassian.net/browse/CIT-130

Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Breast / Ovarian cancer GCEP, accessed 6.28.2023

Clinical Validity Scoring Notes and points

Not provided

Source: ClinGen Breast / Ovarian cancer GCEP, accessed 6.28.2023

Clinical Validity Points Total

8

Source: ClinGen Breast / Ovarian cancer GCEP, accessed 6.28.2023

Clinical Validity Classification

Moderate

Note, NCCN guidelines v3. States strength is strong.

Source: ClinGen Breast / Ovarian cancer GCEP, accessed 6.28.2023

Molecular Mechanism

Loss of function

26720728 - 1915 women with ovarian cancer (OC). Variant frequencies compared to the ESP and ExAC databases. 12 had variants in PALB2, and variants were significantly increased in OC. Supplement table eTable1 shows variants identified, with 11 truncating, frameshift, or deletion variants. NMD+ variants for scoring (not all encompassing): [1] c.757delAG p.(Leu253Ilefs*3), PTC in exon 4. [2] c.1050_1053delAACA p.(Thr351Argfs*4) [3]c.3256C>T p.R1086X [4] c.1479delC p.(Thr494Leufs*67) [5] c.1240C>T p.R414X [6] c.751C>T p.Q251X [7] c.3113G>A p.W1038X

30733081 - Variants in PALB2 were associated with a moderate risk of ovarian cancer (OR 2.134). Fig 3 shows most variants were nonsense and frameshift.

33670479 - Ovarian cancer risk increased in individuals with mutations in PALB2. OR 3.34; 95% CI:1.06–14.68;p=0.06. Additional frameshift variants c.172_175delTTGT, c.509_510delGA.

16793542 - In vitro cellular functional study. PALB2 co-localizes with BRCA2, promotes its localization and stability, and enables recombinational repair and checkpoint functions.

17287723 - c.1592delT is a recurrent variant in Finnish individuals with breast cancer. Ovarian cancer reported in 1 family member (Fig 2)

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

See breast cancer description above (describes br, ov, and fanc)

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06.28.2023 https://broadinstitute.atlassian.net/browse/CIT-130

Inheritance

Autosomal recessive

Prevalence

 1-9 / 1 000 000

Source: ORPHA:84

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP accessed 06.28.2023

Clinical Validity Scoring Notes and points

There is abundant evidence published associating the PALB2 gene with Fanconi anemia complementation group N, since the gene-disease relationship was first proposed by Xia et al. (2007). Multiple case level studies have been performed with FA patients that have variants in the PALB2 gene. A significant amount of case-level data is available, however the maximum points for genetic evidence has been reached (12 points). BRCA1, BRCA2, BRIP1 and RAD51C have also been established as FA genes in the FA/BRCA DNA repair pathway. No full length PALB2 protein was detected in patient (EUFA1341)'s lymphoblasts and fibroblasts. The patients cells also show hypersensitivity to cross-linking agents and lacked BRCA2. Palb2-/-mouse model have been established to show consistent phenotypes with FA patients and Brca1 and Brca2 knockout mice including mesoderm differentiation defect and early embryonic lethality. Introduction of wild-type PALB2 into EUFA1341 fibroblasts cells normalized the association of BRCA2 with the chromatin/nuclear matrix fraction, the ability to form Rad51 foci and the sensitivity to MMC. PALB2 ∆ChAM did not rescue the sensitivity phenotype. All of these types of evidence are consistent with a definitive relationship between the PALB2 gene and Fanconi anemia complementation group N.

Source: ClinGen Hereditary Cancer GCEP accessed 06.28.2023

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer GCEP accessed 06.28.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP accessed 06.28.2023

Molecular Mechanism

Loss of function

Summary: 9 NMD+ variants in patients with FA. Cell studies performed in lymphoblasts and fibroblasts from affected individuals shows reduced levels of PALB2, and introduction of WT restores function.

• PMID: 17200671 - Biallelic variants in PALB2 cause Fanconi anemia (FA-N subtype). Investigated candidate genes for cohort of patients with FA and chidhood embryonal tumors negative for BRCA2 variants. Sequenced PALB2 and identified variants in 7 families, 4 with truncating variants. All confirmed in trans. NMD+ truncations in table 1: [1] 395delT p.(Val132Alafs*45), PTC in exon 4. [2] 757_758del p.(Leu253Ilefs*3), PTC in exon 4. [3] 2257C-T R753X, exon 5. [4] c.2393_2394insCT p.(Thr799Leufs*53), PTC in exon 6. [5] 2521del p.(Thr841Glnfs*10), PTC in exon 6 [6] 2962C-T Q988X, exon 9. [7]3116delA p.(Asn1039Ilefs*2). NMD- variants: 3549C-G Y1183X, 3323delA p.(Tyr1108Serfs*16)

• PMID: 17200672 - Fanconi anemia. Family EUFA1341, proband with FA and het carriers with cancer (breast x2, prostate, esophagus, stomach). Protein blotting in FA patient, full length PALB2 was not detected in lymphoblasts and fibroblasts from affected individual. BRCA2 levels were also reduced in lymphoblasts, and mislocalized in fibroblasts. Rad51 focus formation by MMC was impaired. Introduction of wt PALB2 normalized association of BRCA2 and ability to form Rad51 foci and sensitivity to MMC. Proband found to harbor Y551X (NMD+) and a large genomic deletion encompassing exons 1-10 (NMD+, OOF and encompasses start codon) (sup fig1 and 2).

Sources: PMID: 17200671, 17200672

Penetrance

(list source/PMID)

HIGH

Source: Bone marrow failure (BMF) occurs at a median age of 7 years, developing in 90% of patients by 40 years of age, ORPHA:84

Age of Onset

(list source/PMID)

Pediatric

Severity

Severe

Source: Orpha:84

Clinical Features

Cellular phenotype: Similar to BRCA2-FA, and distinguising feature from other FA subtypes. Elevated spontaneous chromosome breakage rates, markedly reduced lymphocyte survival, increased chromosome breakage on exposure to MMC. No formation of RAD51 loci in PALB2- deficient fibroblasts after ionizing radiation (PMID: 17200671).

Bone marrow failure - aplastic anemia, neutropenia, thrombocytopenia, myelodysplastic syndrome

Cancer susceptibility - acute myeloid leukemia, solid tumors (head and neck; skin, GU, liver). High risk of solid tumors compared to other Fanconi anemia subtypes due to variants in other genes (PMID: 17200671)

Physical anomalies -

• Growth - pre/post natal short stature, low birth weight

• skin: hypopigmentation, cafe-au-lait spots, generalized hyperpigmentation

• Skeletal: Malformed thumbs, absent/hypoplastic radii, other hand malformations, lower limb syndactyly, abnormal toes, club feet, congenital hip dyslocation

• Microcephaly

• Ophthalmic - microphthalmia, cataracts, astigmatism strabismus, epicanthal folds, hypo or hypertelorism

• GU: malformed or absent kidneys, other defects of urinary tract,

• GI - gastrointestinal abnormalities

• Endocrine disorders

• Congenital heart defects

• Eye - small or abnormally shaped eyes

• Ears - malformed ears or hearing loss

• CNS abnormalities

Developmental delay and/or intellectual disability

Sources: NCBI - WWW Error Blocked Diagnostic, PMID: 17200671

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

See breast cancer description above (describes br, ov, and fanc)

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06.28.2023 https://broadinstitute.atlassian.net/browse/CIT-130