This variant deletes 1 nucleotide in exon 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 27553368). 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.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 7
- First in ClinVar:
- Oct 10, 2018
- Most recent Submission:
- Mar 4, 2023
- Last evaluated:
- Jun 24, 2022
- Accession:
- VCV000484161.21
- Variation ID:
- 484161
- Description:
- 1bp deletion
Help
NM_024675.4(PALB2):c.1192del (p.Val398fs)
- Allele ID
- 477697
- Variant type
- Deletion
- Variant length
- 1 bp
- Cytogenetic location
- 16p12.2
- Genomic location
- 16: 23635354 (GRCh38) GRCh38 UCSC
- 16: 23646675 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.1192del MANE Select NP_078951.2:p.Val398fs frameshift NM_024675.4:c.1192delG MANE Select NM_024675.3:c.1192delG NC_000016.10:g.23635354del NC_000016.9:g.23646675del NG_007406.1:g.11004del LRG_308:g.11004del LRG_308t1:c.1192del LRG_308p1:p.Val398fs - Protein change
- V398fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:23635353:C:
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA658658427
- dbSNP: rs1555461407
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Jun 24, 2022 | RCV000565917.15 | |
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Dec 2, 2021 | RCV000818431.14 | |
| Pathogenic | 1 | no assertion criteria provided | - | RCV001357628.9 | |
| Pathogenic | 1 | criteria provided, single submitter | Jul 6, 2021 | RCV002245019.9 | |
| Pathogenic | 1 | criteria provided, single submitter | Feb 11, 2022 | RCV002275087.9 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140042.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Jun 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001358483.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 4 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 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 27553368). 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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|
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Pathogenic
(Jul 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512643.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderate
Geographic origin: Brazil
|
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Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000670611.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.1192delG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1192, causing … (more)
The c.1192delG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1192, causing a translational frameshift with a predicted alternate stop codon (p.V398Cfs*26). 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)
Number of individuals with the variant: 1
|
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Pathogenic
(Dec 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000959045.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Val398Cysfs*26) 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.Val398Cysfs*26) 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 breast cancer (PMID: 27553368). ClinVar contains an entry for this variant (Variation ID: 484161). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002562564.2
First in ClinVar: Aug 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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; Not … (more)
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33084842, 27553368) (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553152.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Val398CysfsX26 variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer … (more)
The PALB2 p.Val398CysfsX26 variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1192del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 398 and leads to a premature stop codon 26 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2-associated breast cancer and is the type of variant expected to cause the disorder. The variant was identified in an affected individual within a family tested by our laboratory, with strong family history of breast cancer and early onset of disease (early 40’s) in the affected proband. In addition, the deleterious nature of this variant has been reported by another reliable source (Myriad). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
Functional evidence
Help| 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 this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity. | Pinto P | Breast cancer research and treatment | 2016 | PMID: 27553368 |
| 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 rs1555461407...
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 Nov 25, 2023