NM_024675.4(PALB2):c.3048del (p.Phe1016fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 12, 2022
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:: RCV000129785.13

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)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184594	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21932393, 22692731, 25428789, 30287823 Citation Link,
SCV000686004	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21932393, 25428789, 27153395, 30128536, 30287823, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184594

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 12, 2022)

germline

clinical testing

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

Citation Link,

SCV000686004

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 21, 2021)

germline

clinical testing

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

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

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 (7)

Details of each submission

From Ambry Genetics, SCV000184594.10

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

Description

The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.F1016Lfs*17). This alteration has been reported in an African American woman diagnosed with invasive breast cancer at age 60 who also had a family history of pancreatic cancer (Zheng Y et al. Cancer 2012;118:1362-70). This variant was also reported in an African American woman with triple negative breast cancer diagnosed over the age of 45 (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000686004.4

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

Description

This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 25428789, 27153395, 30128536, 30287823). In a breast cancer case-control study, this variant was identified in 1/7051 female breast cancer cases and was absent in any controls (PMID: 30287823). This variant has been identified in 1/246228 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.

#	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: Jun 17, 2024

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