16-23603528-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024675.4(PALB2):c.3492G>A(p.Trp1164Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23603528-C-T is Pathogenic according to our data. Variant chr16-23603528-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3492G>A	p.Trp1164Ter	stop_gained	13/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3492G>A	p.Trp1164Ter	stop_gained	13/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	This sequence change creates a premature translational stop signal (p.Trp1164*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246354). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 07, 2022	This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2022	The p.W1164* pathogenic mutation (also known as c.3492G>A), located in coding exon 13 of the PALB2 gene, results from a G to A substitution at nucleotide position 3492. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This stop codon occurs at the 3' terminus of PALB2, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 23 amino acids of the protein. However, these last 23 amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6). Truncating mutations located downstream of this alteration have been identified in individuals with breast cancer, pancreatic cancer, and Fanconia anemia (Hofstatter EW et al. Fam. Cancer. 2011 Jun;10:225-31; Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Dudley B et al. Cancer. 2018 Apr;124:1691-1700; Reid S et al. Nat. Genet. 2007 Feb;39:162-4). As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2016

This variant is denoted PALB2 c.3492G>A at the cDNA level and p.Trp1164Ter (W1164X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA) , and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene in the last exon, and nonsense-mediated decay is not expected to occur, it is significant since the last 23 amino acids are no longer translated. Furthermore, the truncation would disrupt the WD7 repeat region, which is required for POLH DNA synthesis stimulation and interaction with RAD51, BRCA2, and POLH (UniProt). Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D
Vest4		0.83
GERP RS		5.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782217; hg19: chr16-23614849;