NM_024675.4(PALB2):c.3048del (p.Phe1016fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 21, 2023
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:: RCV000412897.14

Allele description [Variation Report for NM_024675.4(PALB2):c.3048del (p.Phe1016fs)]

NM_024675.4(PALB2):c.3048del (p.Phe1016fs)

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.3048del (p.Phe1016fs)

HGVS:

NC_000016.10:g.23621430del
NG_007406.1:g.24931del
NM_024675.4:c.3048delMANE SELECT
NP_078951.2:p.Phe1016fs
NP_078951.2:p.Phe1016fs
LRG_308t1:c.3048del
LRG_308:g.24931del
LRG_308p1:p.Phe1016fs
NC_000016.9:g.23632748del
NC_000016.9:g.23632751del
NM_024675.3:c.3048del
NM_024675.3:c.3048delT
p.F1016LFS*17

Protein change:

F1016fs

Links:

dbSNP: rs515726104

NCBI 1000 Genomes Browser:

rs515726104

Molecular consequence:

NM_024675.4:c.3048del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000490686	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 21, 2023)	germline	clinical testing	Citation Link,
SCV001134549	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 13, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 22692731, 21932393, 25428789, 25186627, 29625052, 32339256, 30128536, 30287823, 29486991, 29922827, 28888541, 27153395, 26689913, 26467025
SCV002067396	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 15, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490686

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 21, 2023)

germline

clinical testing

Citation Link,

SCV001134549

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jun 13, 2023)

unknown

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV002067396

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 15, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families.

Catucci I, Milgrom R, Kushnir A, Laitman Y, Paluch-Shimon S, Volorio S, Ficarazzi F, Bernard L, Radice P, Friedman E, Peterlongo P.

Fam Cancer. 2012 Sep;11(3):483-91. doi: 10.1007/s10689-012-9540-8.

PubMed [citation]

PMID:: 22692731

Novel germline PALB2 truncating mutations in African American breast cancer patients.

Zheng Y, Zhang J, Niu Q, Huo D, Olopade OI.

Cancer. 2012 Mar 1;118(5):1362-70. doi: 10.1002/cncr.26388. Epub 2011 Aug 26.

PubMed [citation]

PMID:: 21932393
PMCID:: PMC3244533

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000490686.6

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

Description

Frameshift 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 individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21932393, 25186627, 37169825); This variant is associated with the following publications: (PMID: 28888541, 21932393, 25186627, 25428789, 24870022, 22692731, 29625052, 26689913, 32339256, 30287823, 30128536, 29486991, 36451132, 27153395, 37169825, 29922827)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134549.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The PALB2 c.3048del (p.Phe1016Leufs*17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32339256 (2020), 30128536 (2019), 30287823 (2018), 29486991 (2018), 28888541 (2017), 27153395 (2016), 25428789 (2015), 25186627 (2015), 21932393 (2012), 22692731 (2012)), head and neck squamous cell carcinoma (PMIDs: 29625052 (2018), 26689913 (2015)), as well as in healthy individuals (PMID: 29922827 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

#	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

From Genetic Services Laboratory, University of Chicago, SCV002067396.1

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

Description

DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid frameshift and creates a premature stop codon 16 amino acids downstream of the mutation, p.Phe1016Leufs*17. This deletion is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The c.3048del sequence change has been identified in an African American woman with breast cancer, and a family history of colorectal cancer, leukemia, and pancreatic cancer (PMID: 21932393). This sequence change is likely causative of susceptibility to breast cancer and pancreatic cancer, however functional studies have not been performed to prove this conclusively.

#	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

Last Updated: Oct 13, 2024

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