ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3539T>C (p.Ile1180Thr)
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.3539T>C (p.Ile1180Thr)
Variation ID: 126747 Accession: VCV000126747.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23603481 (GRCh38) [ NCBI UCSC ] 16: 23614802 (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 Apr 19, 2014 Aug 11, 2024 Apr 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3539T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Ile1180Thr missense NC_000016.10:g.23603481A>G NC_000016.9:g.23614802A>G NG_007406.1:g.42877T>C LRG_308:g.42877T>C LRG_308t1:c.3539T>C LRG_308p1:p.Ile1180Thr - Protein change
- I1180T
- Other names
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- Canonical SPDI
- NC_000016.10:23603480:A:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
5899 | 5940 |
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 21, 2023 | RCV000114633.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2023 | RCV000479423.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 24, 2024 | RCV000569135.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 23, 2022 | RCV001824604.2 |
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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Uncertain significance
(Jul 31, 2018)
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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: SCV000568195.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted PALB2 c.3539T>C at the cDNA level, p.Ile1180Thr (I1180T) at the protein level, and results in the change of an Isoleucine to … (more)
This variant is denoted PALB2 c.3539T>C at the cDNA level, p.Ile1180Thr (I1180T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was observed in a male with breast cancer (Silvestri 2010). PALB2 Ile1180Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the WD7 repeat, the region of interaction with RAD51, BRCA2 and POLH, and the region required for stimulation of POLH DNA synthesis (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Ile1180Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Sep 12, 2018)
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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: SCV000908454.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jan 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074415.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: PALB2 c.3539T>C (p.Ile1180Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PALB2 c.3539T>C (p.Ile1180Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3539T>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with male breast cancer/breast cancer (example, Silvestri_2010, Sandoval_2021, Rizzolo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/PALB2-related disorders. Multiple publications report experimental evidence evaluating an impact on protein function (example, Boonen_2019, Wiltshire_2020). The most pronounced variant effect results in high homologous recombination activity ascertained at levels ranging from 70-80% of wild-type depending upon the study. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 08, 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: SCV004222347.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast cancer, male breast cancer, and kidney cancer (PMIDs: 20180015 (2010), 30613976 (2019), … (more)
In the published literature, this variant has been reported in individuals with breast cancer, male breast cancer, and kidney cancer (PMIDs: 20180015 (2010), 30613976 (2019), 33606809 (2021), and 32830346 (2021)). Studies have shown that this variant has no significant effect on PALB2 function using an HDR assay or PARP inhibitor sensitivity assay (PMIDs: 31757951 (2019), 31586400 (2019), and 31636395 (2020)). The frequency of this variant in the general population, 0.000004 (1/251458 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Sep 11, 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: SCV000814107.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1180 of the PALB2 protein (p.Ile1180Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1180 of the PALB2 protein (p.Ile1180Thr). This variant is present in population databases (rs180177139, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 20180015, 33606809). ClinVar contains an entry for this variant (Variation ID: 126747). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400, 31757951). 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. (less)
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Uncertain significance
(Nov 21, 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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Baylor Genetics
Accession: SCV005055039.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Apr 24, 2024)
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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: SCV000663364.6
First in ClinVar: Jan 01, 2018 Last updated: Aug 11, 2024 |
Comment:
The p.I1180T variant (also known as c.3539T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide … (more)
The p.I1180T variant (also known as c.3539T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide position 3539. The isoleucine at codon 1180 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in cohorts of individuals diagnosed with breast cancer, male breast cancer and kidney cancer (Silvestri V et al. Breast Cancer Res. Treat., 2010 Jul;122:299-301; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16). This alteration was found to be functionally inconclusive in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). In another study, this alteration was found to be functionally normal by a homology-directed DNA repair (HDR) assay and a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(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: SCV001193425.1
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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Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis. | Sandoval RL | PloS one | 2021 | PMID: 33606809 |
Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity. | Smith PS | Genes, chromosomes & cancer | 2021 | PMID: 32830346 |
Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction. | Boonen RACM | Frontiers in molecular biosciences | 2020 | PMID: 33195396 |
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 |
Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. | Boonen RACM | Nature communications | 2019 | PMID: 31757951 |
A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor. | Rodrigue A | Nucleic acids research | 2019 | PMID: 31586400 |
The Tumor Suppressor PALB2: Inside Out. | Ducy M | Trends in biochemical sciences | 2019 | PMID: 30638972 |
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. | Gadd S | Nature genetics | 2017 | PMID: 28825729 |
PALB2 mutations in male breast cancer: a population-based study in Central Italy. | Silvestri V | Breast cancer research and treatment | 2010 | PMID: 20180015 |
Text-mined citations for rs180177139 ...
HelpRecord last updated Sep 08, 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.