ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3426_3429del (p.Leu1142fs)
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
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NM_024675.4(PALB2):c.3426_3429del (p.Leu1142fs)
Variation ID: 185799 Accession: VCV000185799.19
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 16p12.2 16: 23603591-23603594 (GRCh38) [ NCBI UCSC ] 16: 23614912-23614915 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 24, 2014 May 1, 2024 Apr 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3426_3429del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Leu1142fs frameshift NM_024675.3:c.3426_3429delACTT NC_000016.10:g.23603591AAGT[1] NC_000016.9:g.23614912AAGT[1] NG_007406.1:g.42760ACTT[1] LRG_308:g.42760ACTT[1] - Protein change
- L1142fs
- Other names
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- Canonical SPDI
- NC_000016.10:23603590:AAGTAAGT:AAGT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PALB2 | - | - |
GRCh38 GRCh37 |
5836 | 5875 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2023 | RCV000133486.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 26, 2021 | RCV000165289.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2023 | RCV000540873.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 3, 2024 | RCV003991017.1 |
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
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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. |
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Pathogenic
(Jun 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601784.2
First in ClinVar: Aug 24, 2014 Last updated: Jan 01, 2022 |
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Pathogenic
(Jan 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568196.5
First in ClinVar: Aug 24, 2014 Last updated: Jan 21, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25099575, 30287823, 30128536, 34196900, 34399810, 29922827) (less)
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Pathogenic
(Sep 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188554.1
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.
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Pathogenic
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000633431.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1142Phefs*20) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu1142Phefs*20) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs751415161, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25099575). This variant is also known as c.3423_3426del. ClinVar contains an entry for this variant (Variation ID: 185799). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004808355.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1142Phefs*20) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu1142Phefs*20) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PALB2 protein. This variant Not observed at significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25099575, 30287823, 30128536, 34196900, 34399810, 29922827). This variant is also known as c.3423_3426del. ClinVar contains an entry for this variant (Variation ID: 185799). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Age: 40-49 years
Sex: female
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Pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000216007.9
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.3426_3429delACTT pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3426 to … (more)
The c.3426_3429delACTT pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3426 to 3429, causing a translational frameshift with a predicted alternate stop codon (p.L1142Ffs*20). This alteration occurs at the 3' terminus of PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation (designated c.3423_3426del) was identified in a series of breast cancer families (Antoniou AC et al. N. Engl. J. Med. 2014 Aug; 371(6):497-506). This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0 in 11,241 female controls of Japanese ancestry; this alteration was not observed in male patients or controls in this study (Momozawa Y et al. Nat Commun. 2018 10;9:4083). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
germline
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SNPedia
Accession: SCV000188560.1
First in ClinVar: Aug 24, 2014 Last updated: Aug 24, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Feb 28, 2020)
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no assertion criteria provided
Method: curation
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not provided
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193409.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
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Pathogenic
(May 13, 2019)
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Flagged submission
flagged submission
Method: curation
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV001193406 appears to be redundant with SCV001193409.
(less)
Notes: SCV001193406 appears to
(...more)
Source: NCBI
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193406.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
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Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. | Foo TK | Oncogene | 2017 | PMID: 28319063 |
Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
Structural basis for recruitment of BRCA2 by PALB2. | Oliver AW | EMBO reports | 2009 | PMID: 19609323 |
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. | Reid S | Nature genetics | 2007 | PMID: 17200671 |
Text-mined citations for rs587776424 ...
HelpRecord last updated May 01, 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.