Classification rationale

BP1 VUS

PALB2 c.1001A>G

PALB2 VCEP BP1_Supporting is applied as this is a missense variant; true pathogenic missense variants in PALB2 are thought to be exceedingly rare.¹ This variant is present in gnomAD v4.1 at an allele frequency of 0.000075 (121/1,613,326 alleles), which exceeds the VCEP PM2 threshold of 0.00000333 but does not meet BS1 (>0.01%) or BA1 (>0.1%) benign population thresholds.² The variant has been observed in multiple cohorts at frequencies comparable to population controls (Balia 2010: 1/95 cases and 1/50 controls; Catucci 2012: 1/96 cases; Hellebrand 2011: 1/818 cases classified as polymorphism).³ In silico predictors REVEL (0.014) and BayesDel (-0.648) are consistent with a benign interpretation, though PALB2 VCEP does not apply PP3/BP4 for missense variants as published predictors have not achieved functional outcome prediction.⁴ No pathogenic criteria are met. With only BP1_Supporting (benign supporting) applied, the overall classification under PALB2 VCEP v1.2.0 is Uncertain Significance (VUS).⁵

BP1 → VUS

1 cspec ↗

2 gnomad_v4 ↗

3 PMID:20852946 ↗PMID:21618343 ↗PMID:22692731 ↗

4 revelbayesdel

5 cspec ↗

Gene diagram · NM_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 7 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

BP1 supporting Benign

PALB2 VCEP BP1 applies to all missense variants. Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional, and true pathogenic missense variants are thought to be exceedingly rare.

PALB2 VCEP BP1 rule: Apply to all missense variantsp.Tyr334Cys is a missense substitution

cspec ↗

Assessed · not applied

Pathogenic

PS4 No case-control study demonstrates significant statistical enrichment of this variant in affected individuals.

PM2 gnomAD v4.1 allele frequency (7.50e-05, 0.0075%) exceeds the PALB2 VCEP PM2_Supporting threshold of ≤1/300,000 (0.000333%).

PP1 No co-segregation data available meeting VCEP thresholds (LOD≥0.3 or LR≥2:1 for AD).

Benign

BA1 gnomAD v4.1 grpmax filtering allele frequency (6.725e-05, 0.006725%) does not exceed the PALB2 VCEP BA1 threshold of >0.1%.

BS1 gnomAD v4.1 grpmax filtering allele frequency (6.725e-05, 0.006725%) does not exceed the PALB2 VCEP BS1 threshold of >0.01%.

BS2 VCEP BS2 requires Fanconi Anemia proband point-table assessment (≥4 points for Strong, 2 for Moderate, 1 for Supporting).

BS4 VCEP BS4 requires quantitative co-segregation analysis with LOD or Bayes Factor values.

N/A · 18 PVS1 · PS1 · PS2 · PS3 · PM1 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 7.50003e-05; MAF= 0.00750%, 121/1613326 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000574557; MAF= 0.05746%, 17/29588 alleles, homozygotes = 0); grpmax FAF= 6.725e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000106259; MAF= 0.01063%, 30/282328 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000386473; MAF= 0.03865%, 4/10350 alleles, homozygotes = 0); grpmax FAF= 0.00012362.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0075% · 121 / 1,613,326
0 hom · FAF 0.0067%

Ashkenazi Jewish 17 / 29,588	0.057%
Remaining individuals 6 / 62,438	0.0096%
European (non-Finnish) 95 / 1,179,698	0.0081%
Admixed American 2 / 59,856	0.0033%
South Asian 1 / 91,040	0.0011%

+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, African/African American)

gnomAD v2.1

0.011% · 30 / 282,328
0 hom · FAF 0.012%

Ashkenazi Jewish 4 / 10,350	0.039%
European (non-Finnish) 23 / 128,918	0.018%
Remaining individuals 1 / 7,212	0.014%
Admixed American 2 / 35,334	0.0057%

+ 4 not observed (African/African American, East Asian, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (9 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 126581)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.014. BayesDel score = -0.648329.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

22692731 ↗ Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

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

33134171 ↗ Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

20852946 ↗ PALB2: a novel inactivating mutation in a Italian breast cancer family. CLINVAR

21618343 ↗ Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. CLINVAR

22241545 ↗ Rare germline mutations in PALB2 and breast cancer risk: a population-based study. CLINVAR

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