16-23629925-A-T

Position:

• chr16-23629925-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2229T>A​(p.Tyr743*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Variant results in nonsense mediated mRNA decay.

• 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:6
• Conservation: PhyloP100: 0.246

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23629925-A-T is Pathogenic according to our data. Variant chr16-23629925-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629925-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2229T>A	p.Tyr743*	stop_gained	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2229T>A	p.Tyr743*	stop_gained	5/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2014	This pathogenic variant is denoted PALB2 c.2229T>A at the cDNA level and p.Tyr743Ter (Y743X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.One mutation in PALB2, also known as FANCN, has been estimated to increase the risk of female breast cancer 2 to 3-fold over the general population (Erkko 2008, Rahman 2007) resulting in a lifetime risk of approximately 25% to 40%. Women with a PALB2 mutation who have a family history of early-onset breast cancer may have a lifetime risk approaching 50% (Byrnes 2008). Heikkinen et al. (2009) found that women with PALB2 mutations, who have been diagnosed with breast cancer, frequently had a high-grade infiltrating ductal carcinoma with 40% overall (20 out of 50) being ER, PR and HER2 negative. Casadei et al. (2011) found that PALB2 mutation carriers are 6-fold more likely to have a family history of pancreatic cancer, 1.3-fold more likely to have a family history of ovarian cancer and 4-fold more likely to have a family history of male breast cancer. Although the association of PALB2 mutations and pancreatic cancer has been established, the exact risks are not yet well-understood (Jones 2009, Slater 2010). Pennington et al. (2014) identified a germline PALB2 mutation in 2 out of 367 patients, unselected for family history, who had a personal history of ovarian cancer, peritoneal cancer, or fallopian tube cancer.Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one affecting each allele) in the PALB2 gene. This condition is characterized by an increased risk for malignancy in children including leukemia and certain solid tumors as well as physical abnormalities and bone marrow failure. If a PALB2 mutation carrier'spartner is also heterozygous for a PALB2 mutation, the risk to have a child with FA is 25% for each pregnancy. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Oct 10, 2018	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 12, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Human Genetics, Hannover Medical School

Jan 07, 2025

PVS1, PM2_Supporting, PM5 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The p.Y743* pathogenic mutation (also known as c.2229T>A), located in coding exon 5 of the PALB2 gene, results from a T to A substitution at nucleotide position 2229. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration was identified in 1 female breast cancer patient out of 10,030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32). This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0000 in 11,241 female controls, in 53 unselected male breast cancer patients and in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was identified in 1 female of Punjabi ethnicity with early onset, triple negative breast cancer and a family history of early onset breast cancer (Rashid MU et al. Cancer Res Treat, 2019 Jul;51:992-1000). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.21	N
Vest4		0.67
GERP RS		4.9

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: rs730881888; hg19: chr16-23641246;