ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3500C>T (p.Thr1167Ile)
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.3500C>T (p.Thr1167Ile)
Variation ID: 482010 Accession: VCV000482010.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23614841 (GRCh37) [ NCBI UCSC ] 16: 23603520 (GRCh38) [ 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 Jan 1, 2018 May 1, 2024 Jun 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3500C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Thr1167Ile missense NC_000016.10:g.23603520G>A NC_000016.9:g.23614841G>A NG_007406.1:g.42838C>T LRG_308:g.42838C>T LRG_308t1:c.3500C>T LRG_308p1:p.Thr1167Ile - Protein change
- T1167I
- Other names
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- Canonical SPDI
- NC_000016.10:23603519: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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
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. |
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PALB2 | - | - |
GRCh38 GRCh37 |
5836 | 5875 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 18, 2021 | RCV000571848.4 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 23, 2023 | RCV000635737.9 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2023 | RCV000756459.11 |
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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Uncertain significance
(Jan 28, 2018)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884281.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The PALB2 c.3500C>T; p.Thr1167Ile variant is reported in the medical literature in an individual with a personal history of breast cancer and low risk based … (more)
The PALB2 c.3500C>T; p.Thr1167Ile variant is reported in the medical literature in an individual with a personal history of breast cancer and low risk based on family history (Tung 2014). The variant is listed as a variant of uncertain significance in the ClinVar database (Variation ID: 482010). The variant is listed in the Genome Aggregation Database in 1 out of 246250 alleles. The threonine at this position is conserved across species and computational algorithms (SIFT, Mutation Taster) predict this variant is deleterious. Additionally, missense variants in this domain have been shown to have reduced function (Park 2014). Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic PALB2 variants are associated with increased risk for breast cancer (MIM#610355). References: Park JY et al. Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene. 2014 Oct 2;33(40):4803-12. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. (less)
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Uncertain significance
(Nov 11, 2019)
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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: SCV001826460.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect: normal homology directed repair activity (Wiltshire 2019); Observed in an individual with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 31636395, 25186627) (less)
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Uncertain significance
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222346.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). One experimental study reports the variant is … (more)
In the published literature, this variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). One experimental study reports the variant is does not impact PALB2 function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.000004 (1/251474 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Mar 23, 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: SCV000757159.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 482010). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1167 of the PALB2 protein (p.Thr1167Ile). (less)
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Uncertain significance
(Oct 18, 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: SCV000666871.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.T1167I variant (also known as c.3500C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide … (more)
The p.T1167I variant (also known as c.3500C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3500. The threonine at codon 1167 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(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: SCV001193421.1
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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Functional characterization of 84 PALB2 variants of uncertain significance. | Wiltshire T | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31636395 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Text-mined citations for rs1308784980 ...
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.