rs180177103

chr16-23634913-C-Achr16-23634913-C-Gchr16-23634913-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024675.4(PALB2):c.1633G>T(p.Glu545Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.143

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 16-23634913-C-A is Pathogenic according to our data. Variant chr16-23634913-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 126611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23634913-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1633G>T	p.Glu545Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1633G>T	p.Glu545Ter	stop_gained	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251444

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:5

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Dec 04, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Glu545*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177103, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 24415441). ClinVar contains an entry for this variant (Variation ID: 126611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in the heterozygous state in individuals with a personal and/or family history of breast and/or pancreatic cancer (Bogdanova et al., 2011; Fernandes et al., 2014; Pinto et al., 2016; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 21165770, 24415441, 24870022, 27553368, 22692731, 23935381, 24763289, 25525159, 28152038, 34567246, 36988593, 29922827, 32885271) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 21, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 22, 2022	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least four individuals affected with breast cancer (PMID: 21165770, 24415441, 27553368, 33471991; Leiden Open Variation Database DB-ID PALB2_010079). This variant has been identified in 1/251444 chromosomes 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	May 25, 2022	The p.E545* pathogenic mutation (also known as c.1633G>T), located in coding exon 4 of the PALB2 gene, results from a G to T substitution at nucleotide position 1633. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation was reported in a German woman who was diagnosed at the age of 83 years with bilateral invasive ductal carcinoma (IDC) with estrogen and progesterone receptor negative tumors (T2N1M0 and T2N0M0). She did not have an apparent family history of breast cancer, but reportedly her maternal grandmother suffered from stomach cancer and her sister died at the age of 67 from a cancer of unknown origin (Bogdanova N et al. Breast Cancer Res Treat. 2011 Apr;126:545-50). This alteration was also seen in a cohort of 1479 patients who underwent PALB2 genetic testing for hereditary breast cancer after previously testing negative for BRCA1 and BRCA2 mutations (Fernandes PH et al. Cancer. 2014 Apr;120:963-7). Additionally, this mutation was identified in a cohort of 80 Portuguese patients with a family history of breast and/or ovarian cancer who underwent multi-gene panel testing after testing negative for the BRCA1 and BRCA2 Portuguese founder mutations (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56). 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. -

PALB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

The PALB2 c.1633G>T variant is predicted to result in premature protein termination (p.Glu545*). This variant has been reported to be causative for breast cancer (Fernandes et al. 2014. PubMed ID: 24415441). This variant has also been reported in an individual with bilateral invasive ductal carcinoma with estrogen and progesterone receptor negative tumors (Bogdanova et al. 2011. PubMed ID: 21165770). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646234-C-A). This variant has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/126611/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Glu545X variant was identified in 3 of 3364 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Bogdanova 2011, Fernandes 2014). The variant was also identified in dbSNP (ID: rs180177103) as With Pathogenic allele, ClinVar (classified as pathogenic by Ambry Genetics, GeneDx, Counsyl, Invitae), LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1 of 246250 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). The p.Glu545X variant leads to a premature stop codon at position 545, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In addition, the variant was found in a patient diagnosed at the age of 83 years as having bilateral invasive ductal carcinoma (IDC) with estrogen and progesterone receptor negative tumors (Bogdanova 2011). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.27

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.20

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.11

MutationTaster

Benign

1.0

Vest4

0.81

GERP RS

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over