ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.1540G>A (p.Gly514Arg)
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(8); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.1540G>A (p.Gly514Arg)
Variation ID: 232748 Accession: VCV000232748.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23635006 (GRCh38) [ NCBI UCSC ] 16: 23646327 (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 Mar 17, 2018 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.1540G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Gly514Arg missense NC_000016.10:g.23635006C>T NC_000016.9:g.23646327C>T NG_007406.1:g.11352G>A LRG_308:g.11352G>A LRG_308t1:c.1540G>A LRG_308p1:p.Gly514Arg - Protein change
- G514R
- Other names
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- Canonical SPDI
- NC_000016.10:23635005:C:T
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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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00011
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
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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 |
5836 | 5875 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 21, 2022 | RCV000214985.14 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Oct 27, 2023 | RCV000589880.13 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV000989570.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 12, 2019 | RCV001027798.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV003224228.1 |
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
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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
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
(Aug 08, 2016)
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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: SCV000699538.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PALB2 c.1540G>A (p.Gly514Arg) variant involves the alteration of a non-conserved nucleotide. The altered amino acid Gly514 is not clocated in any known … (more)
Variant summary: The PALB2 c.1540G>A (p.Gly514Arg) variant involves the alteration of a non-conserved nucleotide. The altered amino acid Gly514 is not clocated in any known domain. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. However, this variant was found in 8/121412 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000691 (8/11578). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, one internal sample carries the variant of interest and a potential pathogenic APC variant (c.646-2A>G), further supporting the neutrality of the variant of interest. Taken together, this variant is classified as VUS-possibly benign. (less)
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001140033.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Mar 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190408.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
Comment:
PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in … (more)
PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-23646327-C-T). This variant amino acid Arginine (Arg) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(Nov 21, 2019)
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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: SCV001470585.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Jan 06, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911468.3
First in ClinVar: May 19, 2019 Last updated: Jun 19, 2021 |
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Uncertain significance
(Feb 21, 2022)
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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: SCV002530621.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PALB2 c.1540G>A (p.G514R) variant has been reported in individuals with breast cancer, pancreatic cancer, colorectal cancer as well as in controls (PMID: 33471991, 32980694, … (more)
The PALB2 c.1540G>A (p.G514R) variant has been reported in individuals with breast cancer, pancreatic cancer, colorectal cancer as well as in controls (PMID: 33471991, 32980694, 33309985, 30287823). It was observed in 27/3459 chromosomes of the Latino subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 232748). In silico tools suggest the impact of the variant on protein function is benign though these predictions have not been confirmed by functional studies. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 17, 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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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003843161.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The PALB2 c.1540G>A (p.Gly514Arg) missense change has a maximum subpopulation frequency of 0.078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The PALB2 c.1540G>A (p.Gly514Arg) missense change has a maximum subpopulation frequency of 0.078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer, prostate cancer, as well as in healthy controls (PMID: 30287823, 31206626, 31214711). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Pancreatic cancer, susceptibility to, 3 Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920310.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in … (more)
PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-23646327-C-T). This variant amino acid Arginine (Arg) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(May 16, 2023)
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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: SCV000292647.14
First in ClinVar: Jul 24, 2016 Last updated: May 27, 2023 |
Comment:
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: 33309985, … (more)
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: 33309985, 32980694, 30287823, 33471991) (less)
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Likely benign
(Jan 18, 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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Invitae
Accession: SCV000550755.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Oct 27, 2023)
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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: SCV003799511.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 02, 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: SCV000276959.7
First in ClinVar: May 29, 2016 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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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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Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. | Fujita M | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2022 | PMID: 33309985 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Text-mined citations for rs756778249 ...
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.