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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000670638Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 20, 2022) 		germlineclinical testing

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

Citation Link,

SCV000685894Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 15, 2020) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000685894.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 8, 2024