NM_024675.4(PALB2):c.1056_1057del (p.Lys353fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 11, 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:: RCV000165605.10

Allele description [Variation Report for NM_024675.4(PALB2):c.1056_1057del (p.Lys353fs)]

NM_024675.4(PALB2):c.1056_1057del (p.Lys353fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.1056_1057del (p.Lys353fs)

Other names:

NM_024675.3:c.1056_1057del

HGVS:

NC_000016.10:g.23635490CT[1]
NG_007406.1:g.10866GA[1]
NM_024675.4:c.1056_1057delMANE SELECT
NP_078951.2:p.Lys353fs
LRG_308:g.10866GA[1]
NC_000016.9:g.23646810_23646811del
NC_000016.9:g.23646811CT[1]
NM_024675.3:c.1056_1057delGA
NM_024675.4:c.1056_1057delGAMANE SELECT
p.E352EFS*8

Protein change:

K353fs

Links:

dbSNP: rs180177099

NCBI 1000 Genomes Browser:

rs180177099

Molecular consequence:

NM_024675.4:c.1056_1057del - 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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Homo sapiens hydroxypyruvate isomerase (putative) (HYI), transcript variant 3, mRNA
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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216339	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 13, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18302019, 19264984, 28779002, 32339256, 33811135 Citation Link,
SCV000690761	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 11, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18302019, 19763884, 28724667, 33811135, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216339

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 13, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000690761

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 11, 2022)

germline

clinical testing

PubMed (5)
[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

Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.

Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP.

Science. 2009 Apr 10;324(5924):217. doi: 10.1126/science.1171202. Epub 2009 Mar 5.

PubMed [citation]

PMID:: 19264984
PMCID:: PMC2684332

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, Easton DF.

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

PubMed [citation]

PMID:: 28779002
PMCID:: PMC5740532

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000216339.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.1056_1057delGA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 1056 to 1057, causing a translational frameshift with a predicted alternate stop codon (p.K353Ifs*7). This mutation was previously reported in multiple individuals with a personal and/ or family history of breast and pancreatic cancers (García MJ et al. Breast Cancer Res. Treat. 2009 Feb;113:545-51; Jones S et al. Science. 2009 Apr;324:217; Decker B et al. J Med Genet. 2017 11;54:732-741; Zhou J et al. Cancer. 2020 07;126:3202-3208; Ng PS et al. J Med Genet. 2021 Apr;:). 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, SCV000690761.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant deletes 2 nucleotides in exon 4 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 individuals and families affected with breast cancer (PMID: 18302019, 19763884, 28724667, 33811135). This variant has been identified in 1/251300 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: Sep 29, 2024

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