NM_024675.4:c.509_510delGA

Variant names:

• chr16-23636035-ATC-A
• rs515726123
• NM_024675.4:c.509_510delGA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO2_Very_StrongO3_Supporting

The NM_024675.4(PALB2):c.509_510delGA (p.Arg170IlefsTer14) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). 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 0.0000186 (AC=30) in the gnomAD database across 1,614,006 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000166. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001366810: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:54 O:1
• Conservation: PhyloP100: -0.0180
• Publications: 10 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: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O2Null variant in tumour suppressor gene		Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 8 citations, oncogene: 1 citations, driver: 3 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 0.
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000017 — very rare (O3 supporting [+1])

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.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 13	Prot: NP_078951.2
	PALB2 NM_001407296.1		c.449_450delGA p.Arg150IlefsTer14	frameshift	Exon 3 of 12	Prot: NP_001394225.1
	PALB2 NM_001407297.1		c.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 12	Prot: NP_001394226.1

PALB2 NM_024675.4

MANE Select

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 13

frameshift

Prot: NP_078951.2

PALB2 NM_001407296.1

HGVSc / HGVSpc.449_450delGAp.Arg150IlefsTer14

Exon rankExon 3 of 12

frameshift

Prot: NP_001394225.1

PALB2 NM_001407297.1

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 12

frameshift

Prot: NP_001394226.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PALB2 ENST00000261584.9	TSL:1MANE Select	c.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 13	Prot: ENSP00000261584.4 UniProt:
	PALB2 ENST00000568219.5	TSL:1	c.-377_-376delGA	5_prime_UTR	Exon 4 of 13	Prot: ENSP00000454703.2 UniProt:
	PALB2 ENST00000561514.3	TSL:5	c.515_516delGA p.Arg172IlefsTer14	frameshift	Exon 4 of 13	Prot: ENSP00000460666.3 UniProt:

PALB2 ENST00000261584.9

TSL:1MANE Select

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 13

frameshift

Prot: ENSP00000261584.4UniProt: Q86YC2

PALB2 ENST00000568219.5

TSL:1

HGVSc / HGVSpc.-377_-376delGA

Exon rankExon 4 of 13

5_prime_UTR

Prot: ENSP00000454703.2UniProt: H3BN63

PALB2 ENST00000561514.3

TSL:5

HGVSc / HGVSpc.515_516delGAp.Arg172IlefsTer14

Exon rankExon 4 of 13

frameshift

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: 0.0000131	AC:2	Hom:0	AN:152126	Cov:32
GnomAD2 exomes	AF: 0.0000358	AC:9	Hom:	AN:251446	Cov:
GnomAD4 exome	AF: 0.0000192	AC:28	Hom:0	AN:1461880	Cov:
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152126	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:17394	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.00	0	113100	0.0000263	5	190460

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
11	-	-	Familial cancer of breast (11)
8	-	-	Hereditary cancer-predisposing syndrome (8)
3	-	-	Breast-ovarian cancer, familial, susceptibility to, 5 (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Malignant tumor of breast (2)
2	-	-	PALB2-related disorder (2)
1	-	-	autosomal dominant PALB2-related cancer predisposition (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Carcinoma of pancreas (1)
1	-	-	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)
1	-	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	-0.018

Showing 2 of 2 scores

Splicing Scores

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

Showing 1 of 1 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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs515726123;

hg19: chr16-23647356;

COSMIC: COSV108015612;

COSMIC: COSV108015612;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar