chr16-23634974-T-C

Variant names:

• chr16-23634974-T-C
• rs45472400
• NM_024675.4:c.1572A>G
• PALB2 p.Ser524Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B4_Strong

The NM_024675.4(PALB2):c.1572A>G (p.Ser524Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene PALB2 is a tumor suppressor gene (CancerMine: 8 TSG, 1 oncogene, 3 driver citations). The gene PALB2 is a known oncogene (CancerMine: 8 TSG, 1 oncogene, 3 driver citations). The gene PALB2 is a cancer driver gene (CancerMine: 8 TSG, 1 oncogene, 3 driver citations). The variant allele was found at a cumulative frequency of 0.00466 (AC=7,529) in the gnomAD database across 1,614,194 control chromosomes, including 18 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00553. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (17 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: -0.526
• Publications: 12 publications found

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PALB2 NM_024675.4	MANE Select	c.1572A>G p.Ser524Ser	synonymous	Exon 4 of 13	Prot: NP_078951.2
	PALB2 NM_001407296.1		c.1512A>G p.Ser504Ser	synonymous	Exon 3 of 12	Prot: NP_001394225.1
	PALB2 NM_001407297.1		c.1572A>G p.Ser524Ser	synonymous	Exon 4 of 12	Prot: NP_001394226.1

PALB2 NM_024675.4

MANE Select

HGVSc / HGVSpc.1572A>Gp.Ser524Ser

Exon rankExon 4 of 13

synonymous

Prot: NP_078951.2

PALB2 NM_001407296.1

HGVSc / HGVSpc.1512A>Gp.Ser504Ser

Exon rankExon 3 of 12

synonymous

Prot: NP_001394225.1

PALB2 NM_001407297.1

HGVSc / HGVSpc.1572A>Gp.Ser524Ser

Exon rankExon 4 of 12

synonymous

Prot: NP_001394226.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PALB2 ENST00000261584.9	TSL:1MANE Select	c.1572A>G p.Ser524Ser	synonymous	Exon 4 of 13	Prot: ENSP00000261584.4 UniProt:
	PALB2 ENST00000568219.5	TSL:1	c.687A>G p.Ser229Ser	synonymous	Exon 4 of 13	Prot: ENSP00000454703.2 UniProt:
	PALB2 ENST00000561514.3	TSL:5	c.1578A>G p.Ser526Ser	synonymous	Exon 4 of 13	Prot: ENSP00000460666.3 UniProt:

PALB2 ENST00000261584.9

TSL:1MANE Select

HGVSc / HGVSpc.1572A>Gp.Ser524Ser

Exon rankExon 4 of 13

synonymous

Prot: ENSP00000261584.4UniProt: Q86YC2

PALB2 ENST00000568219.5

TSL:1

HGVSc / HGVSpc.687A>Gp.Ser229Ser

Exon rankExon 4 of 13

synonymous

Prot: ENSP00000454703.2UniProt: H3BN63

PALB2 ENST00000561514.3

TSL:5

HGVSc / HGVSpc.1578A>Gp.Ser526Ser

Exon rankExon 4 of 13

synonymous

Prot: ENSP00000460666.3UniProt: A0AA52I2C1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00308	AC:468	Hom:1	AN:152184	Cov:32
GnomAD2 exomes	AF: 0.00320	AC:805	Hom:	AN:251492	Cov:
GnomAD4 exome	AF: 0.00483	AC:7061	Hom:17	AN:1461892	Cov:33
GnomAD4 genome	AF: 0.00307	AC:468	Hom:1	AN:152302	Cov:32
TOPMed (Bravo)	AF: 0.00298	AC:790	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00378	AC:498	Hom:0	AN:131614	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00214	AC:5	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00339	AC:44	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.00115	AC:4	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00200	AC:4	Hom:	AN:2000	Cov:
Turkish Variome	AF: 0.000892	AC:6	Hom:0	AN:6724	Cov:
UK10K	AF: 0.00622	AC:47	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00396 *	44	11112	0.00454 *	80	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00500	142	28420	0.00503	145	28844
Epi25(Epilepsy)	0.00386	162	41958	0.00474	317	66888
SCHEMA(Schizophrenia)	0.00359	438	121852	0.00392	747	190740

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not provided (11)
-	-	6	not specified (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Familial cancer of breast (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.2
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.63
GPN-Star LLR	N/A	0.48
GPN-Star score	N/A	-0.48
Mutation Taster	N/A	100/0	polymorphism
PhyloP100	Benign	-0.53
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 normal (RUO)

1 no calibration

2 assays found for this variant.

Research-use-only (RUO) calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Saturation Genome Editing of PALB2 scores

Saturation Genome Editing of PALB2

• Gene: PALB2
• Assay type: Cell proliferation assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 0.00708

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

BS3 strongFunctionally normalRUO ExCALIBR calibration: BS3 Strong (-6)

Nucleotide level

Saturation Genome Editing of PALB2 scores

Saturation Genome Editing of PALB2

• Gene: PALB2
• Assay type: Cell proliferation assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 0.00708

Classified as

normalFunctionally Normal

This score is at approximately the 69th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs45472400;

hg19: chr16-23646295;

COSMIC: COSV104552865;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar