NM_024675.4(PALB2):c.3026del (p.Pro1009fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 22, 2021
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:: RCV000584711.7

Allele description [Variation Report for NM_024675.4(PALB2):c.3026del (p.Pro1009fs)]

NM_024675.4(PALB2):c.3026del (p.Pro1009fs)

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.3026del (p.Pro1009fs)

HGVS:

NC_000016.10:g.23621453del
NG_007406.1:g.24909del
NM_024675.4:c.3026delMANE SELECT
NP_078951.2:p.Pro1009fs
NP_078951.2:p.Pro1009fs
LRG_308t1:c.3026del
LRG_308:g.24909del
LRG_308p1:p.Pro1009fs
NC_000016.9:g.23632770del
NC_000016.9:g.23632774del
NM_024675.3:c.3026del
NM_024675.3:c.3026delC
p.P1009LfsX6

Protein change:

P1009fs

Links:

dbSNP: rs180177131

NCBI 1000 Genomes Browser:

rs180177131

Molecular consequence:

NM_024675.4:c.3026del - 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
SCV000690893	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002753894	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21285249, 22692731, 26681312, 31757951 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000690893

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

clinical testing

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

SCV002753894

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 22, 2021)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.

Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA, King MC.

Cancer Res. 2011 Mar 15;71(6):2222-9. doi: 10.1158/0008-5472.CAN-10-3958. Epub 2011 Feb 1.

PubMed [citation]

PMID:: 21285249
PMCID:: PMC3059378

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000690893.3

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

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. This variant has not been identified 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

From Ambry Genetics, SCV002753894.2

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

Description

The c.3026delC pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3026, causing a translational frameshift with a predicted alternate stop codon (p.P1009Lfs*6). This alteration has been observed in multiple individuals and families with high risk breast cancer (Casadei S et al. Cancer Res, 2011 Mar;71:2222-9; Catucci I et al. Fam Cancer, 2012 Sep;11:483-91; Susswein LR et al. Genet Med, 2016 08;18:823-32). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally abnormal. In a PARP inhibitor sensitivity assay, this alteration was found to be functionally abnormal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Last Updated: Sep 8, 2024

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