Classification rationale

BP1BP4 Likely Benign

PALB2 c.829G>A missense · exon 4

BP1 (Supporting): missense change (p.Asp277Asn); the PALB2 rules apply BP1 to all missense variants. BP4 (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact. Overall: Likely Benign, produced by Rule19 (at least two supporting benign criteria, BP1 plus BP4).

BP1 + BP4 → Likely Benign

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

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 10 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BP1 supporting Benign

Met (Supporting): BP1 applies to all missense variants under the PALB2 rules, and c.829G>A is missense (p.Asp277Asn).

The PALB2 Version 1.2 VCEP BP1 rule states: Apply to all missense variants.Case normalization identifies NM_024675.4:c.829G>A as NP_078951.2:p.(Asp277Asn), confirming a missense consequence.

cspec ↗

BP4 supporting Benign

Met (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact.

PALB2 VCEP BP4: splice analysis must be considered for all variant types and BP4 is assigned for no predicted splice impact at SpliceAI <=0.1; the VCEP does not permit missense protein-predictor BP4 evidence for PALB2.SpliceAI for NM_024675.4:c.829G>A reports a maximum delta score of 0.002, below the VCEP BP4 cutoff of 0.1.REVEL 0.006 and BayesDel -0.862298 were not counted, preventing duplicate computational evidence and respecting the VCEP exclusion of PALB2 missense protein predictors; BayesDel lacks a verified calibrated threshold publication/table in this case.

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 5 not assessed

Pathogenic

PVS1 Not met: c.829G>A is a missense change (p.Asp277Asn), not a loss-of-function variant, with no predicted splice defect (SpliceAI max delta 0.002).

PS4 Not assessed: no case-control study reporting this exact variant was available to test the required p<=0.05 with risk ratio >=3.

PM2 Not met: gnomAD v4.1 total allele frequency 0.000805% exceeds the PM2 Supporting cutoff of <=0.000333% (1 in 300,000).

PM3 Not assessed: no biallelic observations, second PALB2 variant, or phase data were available for the recessive Fanconi anemia condition.

PP1 Not assessed: no segregation evidence (affected relatives, LOD score, or Bayes factor) was available.

PP3 Not met: SpliceAI max delta 0.002 falls below the >=0.2 threshold required for PP3 splice evidence.

Benign

BA1 Not met: gnomAD v4.1 grpmax FAF 0.00255% is well below the >0.1% BA1 population-frequency threshold.

BS1 Not met: gnomAD v4.1 grpmax FAF 0.00255% is below the >0.01% BS1 population-frequency threshold.

BS2 Not assessed: no healthy adults with this genotype and adequate age context were documented; population databases cannot be used for BS2.

BS4 Not assessed: no family data showing absence of segregation (LOD score or Bayes factor) were available.

N/A · 16 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 8.05478e-06; MAF= 0.00081%, 13/1613948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.6745e-05; MAF= 0.00667%, 5/74912 alleles, homozygotes = 0); grpmax FAF= 2.55e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.12158e-05; MAF= 0.00212%, 6/282808 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01282e-05; MAF= 0.00801%, 2/24960 alleles, homozygotes = 0); grpmax FAF= 3.98e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00081% · 13 / 1,613,948
0 hom · FAF 0.0026%

African/African American 5 / 74,912	0.0067%
Admixed American 1 / 59,978	0.0017%
European (non-Finnish) 7 / 1,180,032	0.00059%

+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0021% · 6 / 282,808
0 hom · FAF 0.004%

African/African American 2 / 24,960	0.008%
Admixed American 1 / 35,440	0.0028%
European (non-Finnish) 3 / 129,132	0.0023%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, 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 (4 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 186811)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.006. BayesDel score = -0.862298.

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 previously been reported in somatic cancers (COSMIC; COSV55167240, n = 3 times).

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 · 8 PMIDs not cited in assessment

23012255 ↗ ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. CLINVAR

23852704 ↗ Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. 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

26689913 ↗ Patterns and functional implications of rare germline variants across 12 cancer types. CLINVAR

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

28944238 ↗ Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. CLINVAR

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

24996433 ↗ RAS testing of colorectal carcinoma—a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group. CLINVAR