16-23636150-GA-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024675.4(PALB2):c.395delT(p.Val132AlafsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V132V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -1.04

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
Fanconi anemia complementation group N
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 16-23636150-GA-G is Pathogenic according to our data. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636150-GA-G is described in CliVar as Pathogenic. Clinvar id is 126748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.395delT	p.Val132AlafsTer45	frameshift_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.395delT	p.Val132AlafsTer45	frameshift_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250634

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111520

Other (OTH)

AF:

0.00

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Apr 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val132Alafs*45) 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 (rs180177085, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 17200671). ClinVar contains an entry for this variant (Variation ID: 126748). For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Fanconi anemia complementation group N

Pathogenic:1

May 13, 2019

Leiden Open Variation Database

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5

Pathogenic:1

Sep 13, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 15, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.395delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 395, causing a translational frameshift with a predicted alternate stop codon (p.V132Afs*45). This mutation has been reported in trans with another PALB2 mutation in an individual with Fanconi anemia (Reid S et al. Nat. Genet. 2007 Feb;39(2):162-4). 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

PhyloP100

-1.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over