chr16-23634974-TGA-GCT

Variant names:

• chr16-23634974-TGA-GCT
• NM_024675.4:c.1570_1572delTCAinsAGC
• PALB2 p.525

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP7

The NM_024675.4(PALB2):c.1570_1572delTCAinsAGC (p.525) variant causes a synonymous change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432
• Publications: 0 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 ACMG Germline Pathogenicity v2019

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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000208 by highest known P/LP ClinVar AF 0.000208) — PM2 moderate.
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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.1570_1572delTCAinsAGC p.525	synonymous	N/A	Prot: NP_078951.2
	PALB2 NM_001407296.1		c.1510_1512delTCAinsAGC p.505	synonymous	N/A	Prot: NP_001394225.1
	PALB2 NM_001407297.1		c.1570_1572delTCAinsAGC p.525	synonymous	N/A	Prot: NP_001394226.1

PALB2 NM_024675.4

MANE Select

HGVSc / HGVSpc.1570_1572delTCAinsAGCp.525

Exon rankN/A

synonymous

Prot: NP_078951.2

PALB2 NM_001407296.1

HGVSc / HGVSpc.1510_1512delTCAinsAGCp.505

Exon rankN/A

synonymous

Prot: NP_001394225.1

PALB2 NM_001407297.1

HGVSc / HGVSpc.1570_1572delTCAinsAGCp.525

Exon rankN/A

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.1570_1572delTCAinsAGC p.525	synonymous	N/A	Prot: ENSP00000261584.4 UniProt:
	PALB2 ENST00000568219.5	TSL:1	c.685_687delTCAinsAGC p.230	synonymous	N/A	Prot: ENSP00000454703.2 UniProt:
	PALB2 ENST00000561514.3	TSL:5	c.1576_1578delTCAinsAGC p.527	synonymous	N/A	Prot: ENSP00000460666.3 UniProt:

PALB2 ENST00000261584.9

TSL:1MANE Select

HGVSc / HGVSpc.1570_1572delTCAinsAGCp.525

Exon rankN/A

synonymous

Prot: ENSP00000261584.4UniProt: Q86YC2

PALB2 ENST00000568219.5

TSL:1

HGVSc / HGVSpc.685_687delTCAinsAGCp.230

Exon rankN/A

synonymous

Prot: ENSP00000454703.2UniProt: H3BN63

PALB2 ENST00000561514.3

TSL:5

HGVSc / HGVSpc.1576_1578delTCAinsAGCp.527

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.43

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr16-23646295;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar