NM_024675.3(PALB2):c.1592delT (p.Leu531Cysfs) AND Familial cancer of breast

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 12, 2017
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000114482.5

Allele description

NM_024675.3(PALB2):c.1592delT (p.Leu531Cysfs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.3(PALB2):c.1592delT (p.Leu531Cysfs)

HGVS:

NC_000016.10:g.23634954delA
NG_007406.1:g.11404delT
NM_024675.3:c.1592delT
NP_078951.2:p.Leu531Cysfs
LRG_308t1:c.1592delT
LRG_308:g.11404delT
LRG_308p1:p.Leu531Cysfs
NC_000016.9:g.23646275delA
p.(Leu531Cysfs*30)
p.L531CFS*30
p.L531CfsX30
r.(?)

Links:

PALB2 database: PALB2_10077; OMIM: 610355.0006; dbSNP: rs180177102

NCBI 1000 Genomes Browser:

rs180177102

Allele Frequency:

0.00012(-)

Molecular consequence:

NM_024675.3:c.1592delT - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: CHEK2-Related Breast Cancer
Identifiers:: MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000148428	PALB2 database	no assertion criteria provided	Pathogenic (Jul 16, 2012)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 17287723, 18628482, 19383810, 22241545
SCV000261895	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Pathogenic (Oct 12, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17287723, 18628482, 19383810, 24153426, 22241545, 26640152, 28492532
SCV000677784	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Apr 4, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18628482, 17287723 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000148428

PALB2 database

no assertion criteria provided

Pathogenic
(Jul 16, 2012)

germline

literature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000261895

Invitae

criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))

Pathogenic
(Oct 12, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000677784

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Pathogenic
(Apr 4, 2017)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype.

Heikkinen T, Kärkkäinen H, Aaltonen K, Milne RL, Heikkilä P, Aittomäki K, Blomqvist C, Nevanlinna H.

Clin Cancer Res. 2009 May 1;15(9):3214-22. doi: 10.1158/1078-0432.CCR-08-3128. Epub 2009 Apr 21.

PubMed [citation]

PMID:: 19383810

Heterozygous mutations in PALB2 cause DNA replication and damage response defects.

Nikkilä J, Parplys AC, Pylkäs K, Bose M, Huo Y, Borgmann K, Rapakko K, Nieminen P, Xia B, Pospiech H, Winqvist R.

Nat Commun. 2013;4:2578. doi: 10.1038/ncomms3578.

PubMed [citation]

PMID:: 24153426
PMCID:: PMC3826652

See all PubMed Citations (7)

Details of each submission

From PALB2 database, SCV000148428.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

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

From Invitae, SCV000261895.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change deletes one nucleotide in exon 4 of the PALB2 mRNA (c.1592delT), causing a frameshift at codon 531. This creates a premature translational stop signal (p.Leu531Cysfs*30) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic. This particular variant has been reported in an individual affected with breast cancer (PMID: 22241545). It has also been reported as a common cause of breast and ovarian cancer in the Finnish population (PMID: 17287723, 18628482, 19383810). Experimental studies using carrier lymphoblastoid cell lines have shown that although this variant does not lead to nonsense mediated decay, the resultant truncated PALB2 protein is unstable, with only 10% being retained (PMID: 24153426). Also, this variant protein showed a reduced ability to bind BRCA2 and failed to support homologous recombination or to restore crosslink repair in PALB2-knockdown cells (PMID: 17287723, 26640152). For these reasons, this variant has been classified 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

From Counsyl, SCV000677784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

Last Updated: Sep 12, 2018

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