Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in at least one individual with multiple primary melanomas (Casula 2019); Not observed in large population cohorts (Lek 2016) This variant is associated with the following publications: (PMID: 31382929)
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3017del (p.Phe1005_Leu1006insTer)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.3017del (p.Phe1005_Leu1006insTer)
Variation ID: 265633 Accession: VCV000265633.21
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23621458 (GRCh38) [ NCBI UCSC ] 16: 23632779 (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 Oct 10, 2016 May 1, 2024 Dec 4, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.3017del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Phe1005_Leu1006insTer nonsense NM_024675.4:c.3017delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024675.3:c.3017delT NC_000016.10:g.23621462del NC_000016.9:g.23632783del NG_007406.1:g.24900del LRG_308:g.24900del - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000016.10:23621457:AAAAA:AAAA
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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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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 |
5921 | 5963 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2019 | RCV000256067.3 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000576650.14 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2023 | RCV001018066.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 4, 2023 | RCV003492021.1 |
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
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322626.9
First in ClinVar: Oct 10, 2016 Last updated: Jul 07, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in at least one individual with multiple primary melanomas (Casula 2019); Not observed in large population cohorts (Lek 2016) This variant is associated with the following publications: (PMID: 31382929) (less)
|
|
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Likely pathogenic
(Nov 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677846.2
First in ClinVar: Jan 07, 2018 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019129.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
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Pathogenic
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202740.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant tumor of breast
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241822.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: PALB2 c.3017delT (p.Leu1006X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: PALB2 c.3017delT (p.Leu1006X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251428 control chromosomes (gnomAD). c.3017delT has been reported in the literature in multiple individuals affected with multiple primary melanomas (Casula_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31382929). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357825.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with multiple primary melanomas (PMID: 31382929). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
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Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591788.5
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1006*) in the PALB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu1006*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 31382929). ClinVar contains an entry for this variant (Variation ID: 265633). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001179247.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.3017delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3017, causing … (more)
The c.3017delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3017, causing a translational frameshift with a predicted alternate stop codon (p.L1006*). This alteration was identified in multiple individuals diagnosed with multiple primary melanomas (Casula M et al. BMC Cancer, 2019 Aug;19:772). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
Variant summary: PALB2 c.3017delT (p.Leu1006X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251428 control chromosomes (gnomAD). c.3017delT has been reported in the literature in multiple individuals affected with multiple primary melanomas (Casula_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31382929). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with multiple primary melanomas (PMID: 31382929). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Leu1006*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 31382929). ClinVar contains an entry for this variant (Variation ID: 265633). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.3017delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3017, causing a translational frameshift with a predicted alternate stop codon (p.L1006*). This alteration was identified in multiple individuals diagnosed with multiple primary melanomas (Casula M et al. BMC Cancer, 2019 Aug;19:772). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in at least one individual with multiple primary melanomas (Casula 2019); Not observed in large population cohorts (Lek 2016) This variant is associated with the following publications: (PMID: 31382929)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
Variant summary: PALB2 c.3017delT (p.Leu1006X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251428 control chromosomes (gnomAD). c.3017delT has been reported in the literature in multiple individuals affected with multiple primary melanomas (Casula_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31382929). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with multiple primary melanomas (PMID: 31382929). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Leu1006*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 31382929). ClinVar contains an entry for this variant (Variation ID: 265633). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.3017delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3017, causing a translational frameshift with a predicted alternate stop codon (p.L1006*). This alteration was identified in multiple individuals diagnosed with multiple primary melanomas (Casula M et al. BMC Cancer, 2019 Aug;19:772). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline and somatic mutations in patients with multiple primary melanomas: a next generation sequencing study. | Casula M | BMC cancer | 2019 | PMID: 31382929 |
| Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
| The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. | Janatova M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2013 | PMID: 24136930 |
| Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. | Xia B | Nature genetics | 2007 | PMID: 17200672 |
| Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. | Reid S | Nature genetics | 2007 | PMID: 17200671 |
| PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. | Rahman N | Nature genetics | 2007 | PMID: 17200668 |
Text-mined citations for rs886039683 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.