ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.839del (p.Asn280fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.839del (p.Asn280fs)
Variation ID: 480243 Accession: VCV000480243.17
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23635707 (GRCh38) [ NCBI UCSC ] 16: 23647028 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 1, 2018 Feb 14, 2024 Apr 5, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024675.4:c.839del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Asn280fs frameshift NM_024675.3:c.839delA NC_000016.10:g.23635712del NC_000016.9:g.23647033del NG_007406.1:g.10651del LRG_308:g.10651del LRG_308t1:c.839del LRG_308p1:p.Asn280fs - Protein change
- N280fs
- Other names
- NM_024675.3(PALB2):c.839del
- p.Asn280fs
- Canonical SPDI
- NC_000016.10:23635706:TTTTTT:TTTTT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
PALB2 | - | - |
GRCh38 GRCh37 |
5762 | 5801 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2021 | RCV000573816.5 | |
Pathogenic (1) |
no assertion criteria provided
|
May 13, 2019 | RCV001030181.2 | |
Pathogenic (4) |
reviewed by expert panel
|
Apr 5, 2023 | RCV001865724.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 26, 2022 | RCV003409833.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Apr 05, 2023)
|
reviewed by expert panel
Method: curation
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
Accession: SCV003915577.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The c.839del (p.Asn280fs) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 4 leading to nonsense mediated … (more)
The c.839del (p.Asn280fs) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 4 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1, PM5_Supporting, PM2_Supporting). (less)
|
|
Pathogenic
(Jan 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001733962.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This variant deletes 1 nucleotide in exon 4 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. (less)
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000663336.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.839delA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 839, causing … (more)
The c.839delA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 839, causing a translational frameshift with a predicted alternate stop codon (p.N280Tfs*8). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer. (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also identified in a cohort of patients with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via a multi-gene panel. (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390). In addition to the information 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. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PALB2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105961.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PALB2 c.839delA variant is predicted to result in a frameshift and premature protein termination (p.Asn280Thrfs*8). This variant has been reported in individuals with ovarian … (more)
The PALB2 c.839delA variant is predicted to result in a frameshift and premature protein termination (p.Asn280Thrfs*8). This variant has been reported in individuals with ovarian and breast cancer (Lilyquist et al. 2017. PubMed ID: 28888541. Table S7; Kwong et al. 2020. PubMed ID: 32068069; Zhou et al. 2020. PubMed ID: 32339256. Table S2). This variant has also been reported in an individual with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/480243/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188484.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
|
|
Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202675.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002230741.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn280Thrfs*8) in the PALB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asn280Thrfs*8) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 480243). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(May 13, 2019)
|
no assertion criteria provided
Method: curation
|
not provided
Affected status: yes
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193027.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: IMGAG.
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. | Janatova M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2013 | PMID: 24136930 |
Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. | Xia B | Nature genetics | 2007 | PMID: 17200672 |
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. | Reid S | Nature genetics | 2007 | PMID: 17200671 |
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. | Rahman N | Nature genetics | 2007 | PMID: 17200668 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/00a3410e-0fb0-4098-8488-6a237f88c850 | - | - | - | - |
Text-mined citations for rs1555461597 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.