ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3340C>T (p.Gln1114Ter)
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.3340C>T (p.Gln1114Ter)
Variation ID: 577564 Accession: VCV000577564.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23607874 (GRCh38) [ NCBI UCSC ] 16: 23619195 (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 Oct 10, 2018 Feb 14, 2024 Jul 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3340C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Gln1114Ter nonsense NC_000016.10:g.23607874G>A NC_000016.9:g.23619195G>A NG_007406.1:g.38484C>T LRG_308:g.38484C>T LRG_308t1:c.3340C>T LRG_308p1:p.Gln1114Ter - Protein change
- Q1114*
- Other names
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- Canonical SPDI
- NC_000016.10:23607873:G:A
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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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- Links
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 |
5762 | 5801 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (1) |
criteria provided, single submitter
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Dec 7, 2022 | RCV000700359.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2023 | RCV000708618.4 |
Submissions - Germline
Classification
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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
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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
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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
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821758.2
First in ClinVar: Oct 10, 2018 Last updated: Apr 22, 2020 |
Comment:
This variant is a single amino acid change from Glutamine to a premature translational stop signal at codon 1114 of the PALB2 protein. This is … (more)
This variant is a single amino acid change from Glutamine to a premature translational stop signal at codon 1114 of the PALB2 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in the PALB2 gene are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). (less)
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Pathogenic
(Dec 07, 2022)
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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: SCV000829111.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*, p.Gln1175*, … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*, p.Gln1175*, p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 26315354; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 577564). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1114*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the PALB2 protein. (less)
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Likely pathogenic
(Jul 20, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004357808.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 12 of the PALB2 gene, creating a premature translation stop signal that is not expected to trigger nonsense-mediated … (more)
This variant changes 1 nucleotide in exon 12 of the PALB2 gene, creating a premature translation stop signal that is not expected to trigger nonsense-mediated decay. The predicted truncated protein impacts the WD40-repeat domain that is functionally important for BRCA2 and RAD51 binding (PMID: 25833843). Other protein truncations in this region have been reported as disease-causing in ClinVar (variation ID: 126734, 450256, 460990, 803231). However, this variant also creates a cryptic splice donor site located 12 nucleotides upstream of the reference intron 12 donor site, that could potentially cause an in-frame deletion of four codons (1114 to 1117) including the premature termination at codon 1114. While this RNA splicing impact has not been confirmed, there is the possibility that the deleterious impact of this nonsense variant may be attenuated by alternative splicing. This variant has been reported in an individual affected with high-risk breast cancer (PMID: 31159747; https://www.preprints.org/manuscript/202105.0156/v2). 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). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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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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Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
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 |
Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. | Prakash R | Cold Spring Harbor perspectives in biology | 2015 | PMID: 25833843 |
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 |
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. | Rahman N | Nature genetics | 2007 | PMID: 17200668 |
[Comparative study of the morphofunctional organization of tissues of different regions of the rat brain in culture]. | Chubakov AR | Zhurnal vysshei nervnoi deiatelnosti imeni I P Pavlova | 1977 | PMID: 202105 |
Text-mined citations for rs1567206756 ...
HelpRecord last updated Feb 20, 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.