ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)
Variation ID: 126708 Accession: VCV000126708.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23621421 (GRCh38) [ NCBI UCSC ] 16: 23632742 (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 Apr 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3054G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Glu1018Asp missense NC_000016.10:g.23621421C>G NC_000016.9:g.23632742C>G NG_007406.1:g.24937G>C LRG_308:g.24937G>C LRG_308t1:c.3054G>C LRG_308p1:p.Glu1018Asp - Protein change
- E1018D
- Other names
- p.E1018D:GAG>GAC
- NM_024675.3(PALB2):c.3054G>C
- p.Glu1018Asp
- Canonical SPDI
- NC_000016.10:23621420:C: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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0.00080 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00016
Exome Aggregation Consortium (ExAC) 0.00030
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00038
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
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
Help
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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Benign (5) |
reviewed by expert panel
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Apr 5, 2023 | RCV000114588.32 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000212821.23 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Dec 31, 2020 | RCV000130354.28 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000286032.13 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000858970.24 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 1, 2019 | RCV001030645.9 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356371.9 | |
PALB2-related disorder
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Likely benign (1) |
no assertion criteria provided
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May 31, 2023 | RCV004529923.2 |
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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Benign
(Apr 05, 2023)
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reviewed by expert panel
Method: curation
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV003915563.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The c.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele … (more)
The c.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>0.001) for BA1, and therefore meets this criterion. This variant has been observed in a homozygous state and phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic by the HBOP VCEP in individuals without Fanconi Anemia (GeneDx, Ambry Genetics, Invitae). This variant is functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BP2_Moderate, BP1) (less)
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Likely benign
(Jan 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067808.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Dec 31, 2020)
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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: SCV002530749.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Oct 23, 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: SCV000211527.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 28825143, 21285249, 22241545, 25575445, 26283626, 23977390, 25356972, 26489409, 26692951, 27783279, 26411315, 27616075, 28580595, 27099641, 26757417, 28664506, … (more)
This variant is associated with the following publications: (PMID: 28825143, 21285249, 22241545, 25575445, 26283626, 23977390, 25356972, 26489409, 26692951, 27783279, 26411315, 27616075, 28580595, 27099641, 26757417, 28664506, 31159747, 31586400, 32566746, 32426482) (less)
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Likely benign
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551637.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Aug 01, 2018)
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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: SCV000822112.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Benign
(Mar 28, 2019)
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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: SCV000699582.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: PALB2 c.3054G>C (p.Glu1018Asp) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the … (more)
Variant summary: PALB2 c.3054G>C (p.Glu1018Asp) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 281404 control chromosomes, predominantly at a frequency of 0.0052 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3054G>C has been reported in the literature predominantly in individuals of East Asian origin affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Tischkowitz_2012, Thompson_2015, Phuah_2013, Nguyen_Dumont_2015, Kraus_2017, Li_2015, Yang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing database (BRCA1 c.2728delC, p.Gln910fsX90), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four of these classified the variant as Benign/Likely benign and three classified it as a VUS. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Sep 04, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474440.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Benign
(Apr 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175576.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Benign
(Jan 30, 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: SCV000253601.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jun 01, 2015)
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criteria provided, single submitter
Method: case-control
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Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes, no
Allele origin:
germline
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Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Accession: SCV000268021.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Geographic origin: Australia
Observation 2:
Number of individuals with the variant: 1
Sex: female
Geographic origin: Australia
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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PALB2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000396077.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Benign
(Apr 19, 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: SCV000902643.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000396076.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(May 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193675.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
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Benign
(Jul 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134550.4
First in ClinVar: Jan 05, 2020 Last updated: Dec 31, 2022 |
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Likely benign
(Jun 27, 2019)
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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: SCV000185205.10
First in ClinVar: Aug 06, 2014 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 31, 2023)
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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: SCV004720445.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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: no
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193337.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551521.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Glu1018Asp variant was identified in 6 of 3322 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Kim 2016, … (more)
The PALB2 p.Glu1018Asp variant was identified in 6 of 3322 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Kim 2016, Li 2015, Nakagomi 2016, Phuah 2013, Thompson 2015). The variant was also identified in the following databases: dbSNP (ID: rs183489969) as With Likely benign, Uncertain significance, other allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, CGLPMCC; classified as likely benign by Illumina; classified as Benign by Invitae), Clinvitae (conflicting interpretations of pathogenicity), Cosmic (none (score 0.69)), MutDB , LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 102 of 277208 chromosomes at a frequency of 0.000368 in the following populations: other in 3 of 6464 chromosomes (freq. 0.00046), European in 1 of 126704 chromosomes (freq. 0.000008), East Asian in 98 of 18868 chromosomes (freq. 0.005), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Glu1018 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the WD40-repeat-containing domain. The variant p.Glu1018Asp was listed as a rare missense variant in a study of 155 Japanese patients with breast and/or ovarian cancers; in this family, the family history of 25 relatives was available but none were reported with breast and/or ovarian cancer (Nakagomi 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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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 |
Validation of a next generation sequencing assay for BRCA1, BRCA2, CHEK2 and PALB2 genetic testing. | Sim WC | Experimental and molecular pathology | 2020 | PMID: 32531196 |
Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. | Boonen RACM | Nature communications | 2019 | PMID: 31757951 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. | Xie Y | Clinical genetics | 2018 | PMID: 28580595 |
Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. | Zhang K | Breast cancer research and treatment | 2017 | PMID: 28825143 |
Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. | Yang XR | Breast cancer research and treatment | 2017 | PMID: 28664506 |
Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer. | Kim H | Breast cancer research and treatment | 2017 | PMID: 27783279 |
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
Analysis of PALB2 mutations in 155 Japanese patients with breast and/or ovarian cancer. | Nakagomi H | International journal of clinical oncology | 2016 | PMID: 26411315 |
Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma. | Yang CY | American journal of translational research | 2015 | PMID: 26692951 |
PALB2 mutations in breast cancer patients from a multi-ethnic region in northwest China. | Li YT | European journal of medical research | 2015 | PMID: 26489409 |
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. | Thompson ER | Breast cancer research : BCR | 2015 | PMID: 26283626 |
Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. | Nguyen-Dumont T | Breast cancer research and treatment | 2015 | PMID: 25575445 |
Prevalence of PALB2 mutations in breast cancer patients in multi-ethnic Asian population in Malaysia and Singapore. | Phuah SY | PloS one | 2013 | PMID: 23977390 |
Rare germline mutations in PALB2 and breast cancer risk: a population-based study. | Tischkowitz M | Human mutation | 2012 | PMID: 22241545 |
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. | Casadei S | Cancer research | 2011 | PMID: 21285249 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b9dcdd59-819e-404b-8621-7ddc360ccb68 | - | - | - | - |
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Text-mined citations for rs183489969 ...
HelpRecord last updated Oct 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.