NM_024675.4(PALB2):c.3362del (p.Gly1121fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 14, 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:: RCV000130740.13

Allele description [Variation Report for NM_024675.4(PALB2):c.3362del (p.Gly1121fs)]

NM_024675.4(PALB2):c.3362del (p.Gly1121fs)

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.3362del (p.Gly1121fs)

Other names:

NM_024675.3(PALB2):c.3362del; p.Gly1121fs

HGVS:

NC_000016.10:g.23603659del
NG_007406.1:g.42700del
NM_024675.4:c.3362delMANE SELECT
NP_078951.2:p.Gly1121fs
LRG_308:g.42700del
NC_000016.10:g.23603658delC
NC_000016.9:g.23614979del
NC_000016.9:g.23614980del
NM_024675.3:c.3362delG
NM_024675.4:c.3362del
p.G1121VFS*3

Links:

dbSNP: rs515726117

NCBI 1000 Genomes Browser:

rs515726117

Molecular consequence:

NM_024675.4:c.3362del - 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
SCV000185631	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 24, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23935836, 24136930, 24549055, 25099575, 25452441, 26283626, 26786923, 29431189, 31636395, 32338768 Citation Link,
SCV000690914	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23935836, 24136930, 24549055, 25452441, 29431189, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185631

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 24, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000690914

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 14, 2022)

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

Breast-cancer risk in families with mutations in PALB2.

Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, et al.

N Engl J Med. 2014 Aug 7;371(6):497-506. doi: 10.1056/NEJMoa1400382.

PubMed [citation]

PMID:: 25099575
PMCID:: PMC4157599

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

Thompson ER, Gorringe KL, Rowley SM, Wong-Brown MW, McInerny S, Li N, Trainer AH, Devereux L, Doyle MA, Li J, Lupat R, Delatycki MB; LifePool Investigators., Mitchell G, James PA, Scott RJ, Campbell IG.

Breast Cancer Res. 2015 Aug 19;17:111. doi: 10.1186/s13058-015-0627-7.

PubMed [citation]

PMID:: 26283626
PMCID:: PMC4539664

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000185631.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The c.3362delG pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3362, causing a translational frameshift with a predicted alternate stop codon (p.G1121Vfs*3). This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 66 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been previously reported in numerous kindreds characterized by early-onset breast cancer, triple negative breast cancer, prostate and/or pancreatic cancer (Blanco A at al. PLoS ONE. 2013 Jul;8:e67538; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9; Lee JEA et al. J. Pathol. 2018 May;245(1):53-60; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). This alteration was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). Based on the supporting evidence, 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, SCV000690914.5

#	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 13 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. This variant has been reported in at least eight individuals affected with breast, ovarian and pancreatic cancer (PMID: 23935836, 24136930, 24549055, 25452441, 29431189, Color internal data). This variant has been identified in 1/251320 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 2, 2024

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