Classification rationale

BP6BP1BS1BA1 Benign

PALB2 c.2027T>C

The PALB2 c.2027T>C (p.Ile676Thr) variant has been reported in ClinVar as Benign, including a reviewed expert panel classification.¹ This variant is present in gnomAD v4.1 with an overall allele frequency of 0.01425% (230/1614160) and a highest observed population frequency of 0.37653% (226/60022 alleles in the Admixed American population), which is above the PALB2 BA1 threshold of 0.1% and the BS1 threshold of 0.01%.² In silico data do not support a splice effect, with a SpliceAI maximum delta score of 0.02; REVEL is 0.003 and BayesDel is -0.705338, but the PALB2 VCEP does not use PP3 or BP4 for missense variants.³

BP6 + BP1 + BS1 + BA1 → Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

PALB2 NM_024675.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 7 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Population frequency is above the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BA1 threshold of 0.1%.

gnomAD v4.1 best subpopulation AF = 0.0037652860617773485 (0.37653%).PALB2 BA1 threshold is grpmax filtering AF > 0.1%.

gnomad_v4 ↗cspec ↗

BS1 strong Benign

Population frequency is above the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BS1 threshold of 0.01%.

gnomAD v4.1 best subpopulation AF = 0.0037652860617773485 (0.37653%).PALB2 BS1 threshold is grpmax filtering AF > 0.01%.

gnomad_v4 ↗cspec ↗

BP1 supporting Benign

This variant is a missense change, and the PALB2 VCEP applies BP1_Supporting to all missense variants because pathogenic PALB2 variation is predominantly truncating and true pathogenic missense variants are considered very rare.

NM_024675.3:c.2027T>C predicts NP_078951.2:p.(Ile676Thr)a missense variant.PALB2 VCEP BP1 rule applies to all missense variants.

cspec ↗

BP6 supporting Benign

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.

PALB2 VCEP marks BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 2 not met · 5 not assessed

Pathogenic

PVS1 This variant is a missense substitution and does not fall within the PALB2 or generic PVS1 null-variant categories.

PS4 No case-control study or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls.

PM2 Population frequency is above the PALB2 PM2_Supporting threshold.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other data meeting the PALB2 PM3 point-based framework.

PP1 No segregation data were identified for this variant.

Benign

BS2 No qualifying observations were identified in healthy adults that could be scored under the PALB2 BS2 point-based framework.

BS4 No quantitative non-segregation data were identified for this variant.

N/A · 17 PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000142489; MAF= 0.01425%, 230/1614160 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00376529; MAF= 0.37653%, 226/60022 alleles, homozygotes = 2); grpmax FAF= 0.00336271.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000728337; MAF= 0.07283%, 206/282836 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.00578606; MAF= 0.57861%, 205/35430 alleles, homozygotes = 1); grpmax FAF= 0.00515383.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.014% · 230 / 1,614,160
2 hom · FAF 0.34%

Admixed American 226 / 60,022	0.38% 2 hom
Remaining individuals 3 / 62,504	0.0048%
East Asian 1 / 44,888	0.0022%

+ 7 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.073% · 206 / 282,836
1 hom · FAF 0.52%

Admixed American 205 / 35,430	0.58% 1 hom
Remaining individuals 1 / 7,222	0.014%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.003. BayesDel score = -0.705338.

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

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance