NM_024675.4(PALB2):c.509_510del (p.Arg170fs) AND PALB2-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 27, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004528797.2

Allele description [Variation Report for NM_024675.4(PALB2):c.509_510del (p.Arg170fs)]

NM_024675.4(PALB2):c.509_510del (p.Arg170fs)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.509_510del (p.Arg170fs)

HGVS:

NC_000016.10:g.23636037_23636038del
NG_007406.1:g.10321_10322del
NM_024675.4:c.509_510delMANE SELECT
NP_078951.2:p.Arg170fs
LRG_308:g.10321_10322del
NC_000016.10:g.23636036_23636037delTC
NC_000016.9:g.23647357_23647358del
NC_000016.9:g.23647358_23647359del
NC_000016.9:g.23647358_23647359delCT
NM_024675.3:c.509_510delGA
NM_024675.4:c.509_510delGAMANE SELECT
p.Arg170Ilefs*14
p.R170IFS*14
p.R170IfsX14

Links:

dbSNP: rs515726123

NCBI 1000 Genomes Browser:

rs515726123

Molecular consequence:

NM_024675.4:c.509_510del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: PALB2-related disorder
Synonyms:: PALB2-related condition; PALB2-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000396132	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20582465, 20412113, 21285249, 24061862, 20122277, 21165770 Citation Link,
SCV004116745	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Jul 23, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000396132

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Apr 27, 2017)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004116745

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Jul 23, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PALB2 analysis in BRCA2-like families.

Adank MA, van Mil SE, Gille JJ, Waisfisz Q, Meijers-Heijboer H.

Breast Cancer Res Treat. 2011 Jun;127(2):357-62. doi: 10.1007/s10549-010-1001-1. Epub 2010 Jun 26.

PubMed [citation]

PMID:: 20582465

PALB2 mutations in European familial pancreatic cancer families.

Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W, Bartsch DK.

Clin Genet. 2010 Nov;78(5):490-4. doi: 10.1111/j.1399-0004.2010.01425.x.

PubMed [citation]

PMID:: 20412113

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000396132.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The PALB2 c.509_510delGA (p.Arg170IlefsTer14) variant results in frameshift and is predicted to result in premature truncation of the protein. The p.Arg170IlefsTer14 variant is reported in at least six studies in which it is found in a heterozygous state in a total of 23 breast cancer patients, two ovarian cancer patients and one pancreatic cancer patient (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014). This variant has not been reported in individuals with Fanconi anemia. The p.Arg170IlefsTer14 variant was found in a heterozygous state in one of 5097 controls and is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant creates a premature stop codon which shortens the PALB2 protein to 182 amino acids from 1186 amino acids. This removes the C-terminal domain which contains the WD40 repeats necessary for BRCA2/PALB2 complex formation. Other deletion variants that remove the C-terminal domain of the PALB2 protein have been shown to have highly reduced BRCA2 binding capacity and be defective in the repair of ds breaks and mitomyocin C-induced damages. To date, all PALB2 variants detected in families with breast cancer or Fanconi anemia have been frameshift or nonsense changes leading to a truncated protein. Based on the evidence and the potential impact of frameshift variants, the p.Arg170IlefsTer14 variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004116745.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PALB2 c.509_510delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg170Ilefs*14). This variant has been reported in multiple unrelated individuals with breast and/or ovarian cancer (see for example - Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Casadei et al. 2011. PubMed ID: 21285249; Cybulski et al. 2015. PubMed ID: 25330149). This variant is reported in 0.0070% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126757/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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