rs180748355

Variant names:

• chr16-23603227-C-A
• rs180748355
• NM_024675.4:c.*232G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_024675.4(PALB2):​c.*232G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 503,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PALB2 NM_024675.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.49
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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

ACMG classification

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (187/152182) while in subpopulation AFR AF = 0.00436 (181/41506). AF 95% confidence interval is 0.00384. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.*232G>T		3_prime_UTR	Exon 13 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.*232G>T		3_prime_UTR	Exon 12 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.*232G>T		3_prime_UTR	Exon 12 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.*232G>T		3_prime_UTR	Exon 13 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.*232G>T		3_prime_UTR	Exon 13 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.*232G>T		3_prime_UTR	Exon 13 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000145 AC: 51 AN: 350862 Hom.: 0 Cov.: 2 AF XY: 0.000108 AC XY: 20 AN XY: 184776

African (AFR) AF: 0.00393 AC: 43 AN: 10932

American (AMR) AF: 0.0000677 AC: 1 AN: 14766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11314

East Asian (EAS) AF: 0.00 AC: 0 AN: 24308

South Asian (SAS) AF: 0.00 AC: 0 AN: 40130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16714

Middle Eastern (MID) AF: 0.000674 AC: 1 AN: 1484

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 210586

Other (OTH) AF: 0.000291 AC: 6 AN: 20628

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74410

African (AFR) AF: 0.00436 AC: 181 AN: 41506

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000832 Hom.: 0

Bravo AF: 0.00146

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial cancer of breast (1)
-	1	-	Fanconi anemia complementation group N (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs180748355; hg19: chr16-23614548;