Classification rationale

BA1BS1BP1 Benign

PALB2 c.2135C>T missense · exon 5

Benign: BA1 is met because the gnomAD grpmax filtering frequency is 0.412487%, above the >0.1% threshold. Benign: BS1 is met at strong strength because the gnomAD grpmax filtering frequency is 0.412487%, above the >0.01% threshold. Benign: BP1 is met at supporting strength because c.2135C>T is a missense substitution.

BA1 + BS1 + BP1 → Benign

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_024675.4 · variants mapped to exon structure

PALB2 NM_024675.4

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BA1 threshold of >0.1%.

gnomAD v4.1 all-comers record for NM_024675.4:c.2135C>T / p.Ala712Val: grpmax FAF=0.00412487 (0.412487%), with the highest observed population frequency in Middle Eastern individuals at AF=0.00560871 (34/6062 alleles).

cspec ↗gnomad_v4 ↗

BS1 strong Benign

Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BS1 threshold of >0.01%.

gnomAD v4.1 all-comers record for NM_024675.4:c.2135C>T / p.Ala712Val: grpmax FAF=0.00412487 (0.412487%), with the highest observed population frequency in Middle Eastern individuals at AF=0.00560871 (34/6062 alleles).

cspec ↗gnomad_v4 ↗

BP1 supporting Benign

Met, Supporting: BP1 applies to all missense variants, and NM_024675.4:c.2135C>T encodes missense p.Ala712Val.

PALB2 CSPEC BP1 rule: Apply to all missense variants.The case evidence identifies NM_024675.4:c.2135C>T (p.Ala712Val/p.A712V) as a missense substitution.

cspec ↗

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

Pathogenic

PS4 Not assessed: the variant was reported in one cohort, but no VCEP-required case-control p-value, effect estimate, or confidence interval is available.

PM2 Not met: the highest gnomAD v4.1 subpopulation AF is 0.560871%, above the VCEP PM2 threshold of 0.000333%.

PM3 Not assessed: the exact variant lacks documented Fanconi Anemia phenotype, pathogenic variant in trans, homozygosity, or phase information required by the VCEP PM3 table.

PP1 Not assessed: the exact-variant report provides one proband but no affected relatives, parental testing, segregation count, LOD, or LR threshold value.

PP3 Not met: SpliceAI maximum delta score 0.028 is below the VCEP PP3 threshold of ≥0.2 for predicted splice impact.

Benign

BS2 Not assessed: gnomAD reports homozygotes, but no Fanconi Anemia BS2 table points can be assigned without proband phenotype and age data.

BS4 Not assessed: no non-segregating relatives, informative meioses, LOD, or LR are reported for comparison with the VCEP BS4 thresholds.

N/A · 18 PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · 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= 0.000195154; MAF= 0.01952%, 315/1614106 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00560871; MAF= 0.56087%, 34/6062 alleles, homozygotes = 1); grpmax FAF= 0.00412487.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000279264; MAF= 0.02793%, 79/282886 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.00138427; MAF= 0.13843%, 10/7224 alleles, homozygotes = 1); grpmax FAF= 0.00041893.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00027156202476645667, 5/18412 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.02% · 315 / 1,614,106
2 hom · FAF 0.41%

Middle Eastern 34 / 6,062	0.56% 1 hom
Ashkenazi Jewish 33 / 29,604	0.11%
Remaining individuals 27 / 62,508	0.043%
Admixed American 24 / 60,016	0.04%
South Asian 21 / 91,076	0.023% 1 hom
European (non-Finnish) 174 / 1,180,012	0.015%
African/African American 2 / 75,012	0.0027%

+ 3 not observed (European (Finnish), Amish, East Asian)

gnomAD v2.1

0.028% · 79 / 282,886
1 hom · FAF 0.042%

Remaining individuals 10 / 7,224	0.14% 1 hom
Ashkenazi Jewish 12 / 10,370	0.12%
Admixed American 12 / 35,440	0.034%
European (non-Finnish) 38 / 129,194	0.029%
South Asian 7 / 30,616	0.023%

+ 3 not observed (African/African American, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.027% · 5 / 18,412
0 hom

Remaining individuals 1 / 1,138	0.088%
South Asian 1 / 1,362	0.073%
European (non-Finnish) 3 / 11,734	0.026%

+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (16 clinical laboratories) and as Benign (5 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 126637)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.041. BayesDel score = -0.761362.

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; COSV99849032, n = 2 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

25356972 ↗ BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

20589654 ↗ Fanconi anemia gene mutations are not involved in sporadic Wilms tumor. CLINVAR

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

25085752 ↗ Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. CLINVAR

25980754 ↗ Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. CLINVAR

26283626 ↗ Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. CLINVAR

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

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