NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 20, 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:: RCV000572212.8

Allele description [Variation Report for NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs)]

NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs)

Gene:

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

Variant type:

Indel

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs)

HGVS:

NC_000016.10:g.23634869_23634870delinsC
NG_007406.1:g.11488_11489delinsG
NM_024675.4:c.1676_1677delinsGMANE SELECT
NP_078951.2:p.Gln559fs
LRG_308:g.11488_11489delinsG
NC_000016.9:g.23646190_23646191delinsC
NM_024675.3:c.1676_1677delAAinsG

Protein change:

Q559fs

Links:

dbSNP: rs515726073

NCBI 1000 Genomes Browser:

rs515726073

Molecular consequence:

NM_024675.4:c.1676_1677delinsG - 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
SCV000670638	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23112754, 26990772 Citation Link,
SCV000685894	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000670638

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 20, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000685894

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]

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

Shared Copy Number Variation in Simultaneous Nephroblastoma and Neuroblastoma due to Fanconi Anemia.

Serra A, Eirich K, Winkler AK, Mrasek K, Göhring G, Barbi G, Cario H, Schlegelberger B, Pokora B, Liehr T, Leriche C, Henne-Bruns D, Barth TF, Schindler D.

Mol Syndromol. 2012 Sep;3(3):120-130. Epub 2012 Aug 23.

PubMed [citation]

PMID:: 23112754
PMCID:: PMC3473353

A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.

Byrd PJ, Stewart GS, Smith A, Eaton C, Taylor AJ, Guy C, Eringyte I, Fooks P, Last JI, Horsley R, Oliver AW, Janic D, Dokmanovic L, Stankovic T, Taylor AM.

PLoS Genet. 2016 Mar;12(3):e1005945. doi: 10.1371/journal.pgen.1005945.

PubMed [citation]

PMID:: 26990772
PMCID:: PMC4798644

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000670638.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1676_1677delAAinsG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.Q559Rfs*2). This alteration has been reported in the homozygous state in an individual with Fanconi anemia who developed Wilm's tumor and medullobastoma; her consanguineous parents were both found to be carriers, and multiple cases of breast and lung cancer were reported in the family (Serra A et al. Mol Syndromol, 2012 Sep;3:120-130). This mutation, designated also as p.Gln559ArgfsTer2, was identified in trans with a hypomorphic PALB2 allele (c.2586+1G>A) in siblings with very mild FA-N (Byrd PJ et al. PLoS Genet., 2016 Mar;12:e1005945). 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, SCV000685894.3

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

Description

This variant is located in the PALB2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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

Last Updated: Sep 8, 2024

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