ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3507_3508del (p.His1170fs)
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.3507_3508del (p.His1170fs)
Variation ID: 140978 Accession: VCV000140978.48
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 16p12.2 16: 23603512-23603513 (GRCh38) [ NCBI UCSC ] 16: 23614833-23614834 (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 Mar 10, 2024 Dec 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3507_3508del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.His1170fs frameshift NM_024675.3:c.3507_3508delTC NC_000016.10:g.23603513AG[1] NC_000016.9:g.23614834AG[1] NG_007406.1:g.42843TC[1] LRG_308:g.42843TC[1] - Protein change
- H1170fs
- Other names
- NP_078951.2:p.His1170PhefsTer19
- Canonical SPDI
- NC_000016.10:23603511:GAGAG:GAG
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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
Help
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
Help
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 |
5755 | 5797 |
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2023 | RCV000129272.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2022 | RCV000133490.22 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2023 | RCV000211073.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 5, 2022 | RCV001849313.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2023 | RCV001781465.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225427.4 |
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. |
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Likely pathogenic
(Jun 01, 2015)
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criteria provided, single submitter
Method: case-control
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Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes
Allele origin:
germline
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Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Accession: SCV000267975.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Australia
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Pathogenic
(Dec 07, 2020)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001348382.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This variant deletes 2 nucleotides in the last coding exon 13 of the PALB2 gene, substituting the last 17 amino acids of the protein with … (more)
This variant deletes 2 nucleotides in the last coding exon 13 of the PALB2 gene, substituting the last 17 amino acids of the protein with 18 different amino acids. This variant may also be known as c.3504_3505del. The variant impacts the C-terminus of the WD40 repeats domain, a known functional domain (PMID: 16793542, 19423707). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals with personal and/or family history of breast and ovarian cancer (PMID: 25099575, 25225577, 26283626, 26315354, 26786923, 29752822, 29431189, 28825143) and prostate cancer (PMID: 24556621), including one family in which the variant segregates with three first-degree relatives with early-onset or bilateral breast cancer (PMID: 25225577). This variant has been identified in 1/31326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Mar 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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PALB2-Related Disorders
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002107149.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.3507_3508del ;p.(His1170Phefs*?) is a null frameshift variant (NMD) in the PALB2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in … (more)
The c.3507_3508del ;p.(His1170Phefs*?) is a null frameshift variant (NMD) in the PALB2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 140978; 25225577; PMID: 26283626; PMID: 25099575; PMID: 24556621; PMID: 26786923)PS4. The variant is present at low allele frequencies population databases (rs587776428 – gnomAD 0.00006579%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 25225577, 24556621) - PP1_moderate. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002504912.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
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Likely pathogenic
(May 18, 2017)
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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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Counsyl
Accession: SCV000677794.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 21, 2022)
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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: SCV000322189.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in an extension of the protein, as the last 17 amino acids are replaced with 18 different amino acids, which … (more)
Frameshift variant predicted to result in an extension of the protein, as the last 17 amino acids are replaced with 18 different amino acids, which disrupts a portion of the seventh WD repeat and the critical region required for interaction with RAD51, BRCA2, POLH, and POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010, Buisson 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26283626, 28825143, 17200671, 26314360, 16793542, 19609323, 26315354, 24556621, 25225577, 25099575, 19423707, 19584259, 24998779, 29431189, 29752822, 32339256, 30982232, 28888541, 20871615, 24485656) (less)
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Likely pathogenic
(Jan 25, 2023)
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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: SCV000184032.10
First in ClinVar: Aug 06, 2014 Last updated: Apr 15, 2023 |
Comment:
The c.3507_3508delTC variant, located in coding exon 13 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 3507 to 3508, … (more)
The c.3507_3508delTC variant, located in coding exon 13 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 3507 to 3508, causing a translational frameshift with a predicted alternate stop codon (p.H1170Ffs*19). This alteration occurs at the 3' terminus of the PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, alters the last 17 amino acids of the protein and results in the elongation of the protein by one amino acid. However, these 3' amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6). This alteration has also been reported in multiple individuals with personal and/or family history suggestive of hereditary breast, ovarian, or prostate cancer (Leongamornlert D et al. Br J Cancer. 2014 Mar 18;110(6):1663-72; Hartley T et al. Hered Cancer Clin Pract. 2014 Aug 28;12(1):19; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11); Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166:865-873; Lee JEA et al. J. Pathol. 2018 May;245:53-60; Li JY et al. Int. J. Cancer. 2019 01;144:281-289; Rowley SM et al. Genet. Med., 2019 04;21:913-922; Yadav S et al. J. Clin. Oncol., 2020 May;38:1409-1418). Further, Hartley et al., reported segregation of this alteration with disease in 4 out of 5 individuals from one family. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581287.2
First in ClinVar: Oct 15, 2022 Last updated: Jul 22, 2023 |
Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001251423.2
First in ClinVar: May 31, 2020 Last updated: Aug 23, 2023 |
Comment:
Criteria applied: PVS1_MOD,PS4,PM2_SUP_MOD,PP1
Clinical Features:
Paresthesia (present) , Pain (present) , Weight loss (present) , Exercise-induced muscle cramps (present) , Tremor (present) , Dysphagia (present) , Hypoesthesia (present) , Strabismus … (more)
Paresthesia (present) , Pain (present) , Weight loss (present) , Exercise-induced muscle cramps (present) , Tremor (present) , Dysphagia (present) , Hypoesthesia (present) , Strabismus (present) , Muscle weakness (present) (less)
Sex: female
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Pathogenic
(Jul 06, 2021)
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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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Baylor Genetics
Accession: SCV004202784.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016520.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 08, 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: SCV000290879.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs*19). While this is not anticipated to result in nonsense mediated decay, it is … (more)
This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PALB2 protein and extend the protein by 1 additional amino acid residues. This variant is present in population databases (rs587781411, gnomAD 0.1%). This frameshift has been observed in individual(s) with breast, ovarian and prostate cancer and breast cancer (PMID: 24556621, 25099575, 25225577, 26283626, 26314354, 26786923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3504_3505del. ClinVar contains an entry for this variant (Variation ID: 140978). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Y1183*) 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
(Sep 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961581.13
First in ClinVar: Oct 08, 2021 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Mar 31, 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: SCV004019688.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein … (more)
This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. Functional studies indicate this variant impacts protein function [PMID: 19423707, 19609323]. (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: SCV000188564.1
First in ClinVar: Aug 24, 2014 Last updated: Aug 24, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(May 13, 2019)
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no assertion criteria provided
Method: curation
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193423.1
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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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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Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer. | Yadav S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2020 | PMID: 32125938 |
Homologous recombination DNA repair defects in PALB2-associated breast cancers. | Li A | NPJ breast cancer | 2019 | PMID: 31428676 |
Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility. | Rowley SM | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30254378 |
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
Molecular analysis of PALB2-associated breast cancers. | Lee JEA | The Journal of pathology | 2018 | PMID: 29431189 |
Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. | Zhang K | Breast cancer research and treatment | 2017 | PMID: 28825143 |
Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care. | Thompson ER | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26786923 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Ischemic preconditioning and thrombosis. | Kristensen SD | VASA. Zeitschrift fur Gefasskrankheiten | 2015 | PMID: 26314354 |
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. | Thompson ER | Breast cancer research : BCR | 2015 | PMID: 26283626 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. | Hartley T | Hereditary cancer in clinical practice | 2014 | PMID: 25225577 |
Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. | Park JY | Biochimica et biophysica acta | 2014 | PMID: 24998779 |
Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. | Leongamornlert D | British journal of cancer | 2014 | PMID: 24556621 |
Structural basis for recruitment of BRCA2 by PALB2. | Oliver AW | EMBO reports | 2009 | PMID: 19609323 |
PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. | Zhang F | Molecular cancer research : MCR | 2009 | PMID: 19584259 |
PALB2 regulates recombinational repair through chromatin association and oligomerization. | Sy SM | The Journal of biological chemistry | 2009 | PMID: 19423707 |
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. | Reid S | Nature genetics | 2007 | PMID: 17200671 |
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Text-mined citations for rs587776428 ...
HelpRecord last updated Mar 17, 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.