PALB2 p.Thr1100Thr

Variant names:

• chr16-23607914-A-C
• rs45516100
• NM_024675.4:c.3300T>G
• PALB2 p.Thr1100Thr

Your query was ambiguous. Multiple possible variants found:

• chr16-23607914-A-C
• chr16-23607914-A-G
• chr16-23607914-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB4_Strong

The NM_024675.4(PALB2):c.3300T>G (p.Thr1100Thr) 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 0.0277 (AC=44,720) in the gnomAD database across 1,614,080 control chromosomes, including 732 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0558. 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 (★★). The variant has been observed in cBioPortal in 2 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 31)
  • Exomes 𝑓: 0.028 (660 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.305
• Publications: 30 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

PALB2-AS1 (HGNC:58305): ()

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: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.0558 — exceeds 1% threshold (B1 applied)
	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.3300T>G p.Thr1100Thr	synonymous	Exon 12 of 13	Prot: NP_078951.2
	PALB2 NM_001407296.1		c.3240T>G p.Thr1080Thr	synonymous	Exon 11 of 12	Prot: NP_001394225.1
	PALB2 NM_001407297.1		c.3228T>G p.Thr1076Thr	synonymous	Exon 11 of 12	Prot: NP_001394226.1

PALB2 NM_024675.4

MANE Select

HGVSc / HGVSpc.3300T>Gp.Thr1100Thr

Exon rankExon 12 of 13

synonymous

Prot: NP_078951.2

PALB2 NM_001407296.1

HGVSc / HGVSpc.3240T>Gp.Thr1080Thr

Exon rankExon 11 of 12

synonymous

Prot: NP_001394225.1

PALB2 NM_001407297.1

HGVSc / HGVSpc.3228T>Gp.Thr1076Thr

Exon rankExon 11 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.3300T>G p.Thr1100Thr	synonymous	Exon 12 of 13	Prot: ENSP00000261584.4 UniProt:
	PALB2 ENST00000568219.5	TSL:1	c.2415T>G p.Thr805Thr	synonymous	Exon 12 of 13	Prot: ENSP00000454703.2 UniProt:
	PALB2 ENST00000561514.3	TSL:5	c.3306T>G p.Thr1102Thr	synonymous	Exon 12 of 13	Prot: ENSP00000460666.3 UniProt:

PALB2 ENST00000261584.9

TSL:1MANE Select

HGVSc / HGVSpc.3300T>Gp.Thr1100Thr

Exon rankExon 12 of 13

synonymous

Prot: ENSP00000261584.4UniProt: Q86YC2

PALB2 ENST00000568219.5

TSL:1

HGVSc / HGVSpc.2415T>Gp.Thr805Thr

Exon rankExon 12 of 13

synonymous

Prot: ENSP00000454703.2UniProt: H3BN63

PALB2 ENST00000561514.3

TSL:5

HGVSc / HGVSpc.3306T>Gp.Thr1102Thr

Exon rankExon 12 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: 0.0254	AC:3870	Hom:72	AN:152138	Cov:31
GnomAD2 exomes	AF: 0.0237	AC:5950	Hom:	AN:251488	Cov:
GnomAD4 exome	AF: 0.0279	AC:40855	Hom:660	AN:1461824	Cov:32
GnomAD4 genome	AF: 0.0254	AC:3865	Hom:72	AN:152256	Cov:31
TOPMed (Bravo)	AF: 0.0260	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0264	AC:3119	Hom:47	AN:118076	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0329	AC:77	Hom:2	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000295	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0233	AC:7	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0280	AC:364	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.00779	AC:28	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0891	AC:179	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122716	Cov:
Turkish Variome	AF: 0.0541	AC:359	Hom:16	AN:6640	Cov:
UK10K	AF: 0.0296	AC:224	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0225 *	250	11112	0.0196 *	345	17618
BipEx(Bipolar disorder (including schizoaffective))	0.0255	724	28420	0.0262	757	28844
Epi25(Epilepsy)	0.0284	1191	41958	0.0275	1841	66888
SCHEMA(Schizophrenia)	0.0241	2966	123312	0.0254	4909	193384

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
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Familial cancer of breast (3)
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 5 (2)
-	-	1	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.64
GPN-Star LLR	N/A	-1.8
GPN-Star score	N/A	1.8
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.30

Showing 8 of 8 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: 0.00428

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: 0.00428

Classified as

normalFunctionally Normal

This score is at approximately the 63th 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: rs45516100;

hg19: chr16-23619235;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar