ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.23C>T (p.Pro8Leu)
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.
Uncertain significance(1); Benign(1); Likely benign(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.23C>T (p.Pro8Leu)
Variation ID: 126652 Accession: VCV000126652.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23641135 (GRCh38) [ NCBI UCSC ] 16: 23652456 (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 Oct 8, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.23C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Pro8Leu missense NC_000016.10:g.23641135G>A NC_000016.9:g.23652456G>A NG_007406.1:g.5223C>T LRG_308:g.5223C>T LRG_308t1:c.23C>T LRG_308p1:p.Pro8Leu - Protein change
- P8L
- Other names
- p.P8L:CCC>CTC
- NP_078951.2:p.Pro8Leu
- Canonical SPDI
- NC_000016.10:23641134: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 0.00013
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD) 0.00051
Trans-Omics for Precision Medicine (TOPMed) 0.00056
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
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
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 |
5906 | 5947 |
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
Help
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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Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000114527.21 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2021 | RCV000160872.14 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2022 | RCV000589826.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225301.2 | |
PALB2-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Mar 22, 2024 | RCV004529922.2 |
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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Likely benign
(Feb 16, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699564.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.23C>T (p.Pro8Leu) in PALB2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. … (more)
Variant summary: The c.23C>T (p.Pro8Leu) in PALB2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is located in the a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.0001801 (20/ 111058 chrs tested), predominantly in individuals of African descent (0.001817; 16/ 8808 chrs tested). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.000156, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pt without strong evidence for causality. The variant is cited as VUS/Likely Benign by reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as Likely Benign. (less)
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Likely benign
(Jan 05, 2016)
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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: SCV000910788.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Likely benign
(Dec 31, 2020)
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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: SCV000211560.14
First in ClinVar: Feb 24, 2015 Last updated: Jul 07, 2021 |
Comment:
Published functional studies demonstrate moderate PARPi sensitivity, moderate interaction with BRCA1, cellular localization similar to wild type, normal response to DNA damage, reduced RAD51 foci … (more)
Published functional studies demonstrate moderate PARPi sensitivity, moderate interaction with BRCA1, cellular localization similar to wild type, normal response to DNA damage, reduced RAD51 foci formation, and normal or decreased HDR activity (Rodrigue 2019, Wiltshire 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32185139, 33169439, 32209438, 31636395, 31658756, 31586400, 23555315, 25503501, 28944238, 28528518, 26315354, 25186627, 21113654) (less)
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Likely benign
(Feb 27, 2019)
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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: SCV001134544.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(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: SCV002504952.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022 |
Number of individuals with the variant: 5
Geographic origin: South Africa
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Likely benign
(Apr 23, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530695.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Dec 13, 2022)
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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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Mendelics
Accession: SCV001140072.2
First in ClinVar: Jan 09, 2020 Last updated: Dec 17, 2022 |
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Likely benign
(Feb 01, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000262327.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(May 12, 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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Ambry Genetics
Accession: SCV000217148.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(May 13, 2019)
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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: SCV001192901.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
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Uncertain significance
(Mar 22, 2024)
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no assertion criteria provided
Method: clinical testing
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PALB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115008.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The PALB2 c.23C>T variant is predicted to result in the amino acid substitution p.Pro8Leu. This variant has been reported in individuals with breast and colorectal … (more)
The PALB2 c.23C>T variant is predicted to result in the amino acid substitution p.Pro8Leu. This variant has been reported in individuals with breast and colorectal cancer; however, a causative association has not been established (Ding et al. 2011. PubMed ID: 21113654; Tung et al. 2014. PubMed ID: 25186627, Supplemental Table 2; Maxwell et al. 2014. PubMed ID: 25503501, Supplemental Table 1; Cock-Rada et al. 2018. PubMed ID: 28528518, Table 2; DeRycke et al. 2017. PubMed ID: 28944238, Supplemental Table S2). Functional studies of this variant are conflicting, with some indicating similar function to wild type protein (Rodrigue et al. 2019. PubMed ID: 31586400). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD. ClinVar classifications range from benign to uncertain, with a consensus of recent classifications pointing toward likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126652/). Although we suspect this alteration is more likely benign, at this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. (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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A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
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 |
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
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 |
Germline mutations in PALB2 in African-American breast cancer cases. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 21113654 |
Text-mined citations for rs150390726 ...
HelpRecord last updated Oct 13, 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.