This variant deletes 1 nucleotide in exon 5 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 breast cancer, and in an individual affected with breast cancer and thyroid cancer (PMID: 25575445, 26681312; Color internal data). This variant has been identified in 2/251492 chromosomes 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
NM_024675.4(PALB2):c.2120del (p.Pro707fs)
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.
(9)
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
9
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.2120del (p.Pro707fs)
Variation ID: 128128 Accession: VCV000128128.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23630034 (GRCh38) [ NCBI UCSC ] 16: 23641355 (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 28, 2016 Jun 17, 2024 Jan 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.2120del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Pro707fs frameshift NM_024675.3:c.2120delC NC_000016.10:g.23630035del NC_000016.9:g.23641356del NG_007406.1:g.16324del LRG_308:g.16324del - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000016.10:23630033:GG: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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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. |
|||
| 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 (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 21, 2023 | RCV000116079.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2023 | RCV000254677.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000409069.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 14, 2018 | RCV001258078.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685920.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 5 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 5 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 breast cancer, and in an individual affected with breast cancer and thyroid cancer (PMID: 25575445, 26681312; Color internal data). This variant has been identified in 2/251492 chromosomes 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)
|
|
|
Pathogenic
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000278671.9
First in ClinVar: Feb 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.2120delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2120, causing … (more)
The c.2120delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2120, causing a translational frameshift with a predicted alternate stop codon (p.P707Lfs*2). This alteration was reported in a woman diagnosed with breast cancer at age 62 from a cohort of 1250 families enrolled in the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res.Treat. 2015 Jan;149(2):547-54). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med. 2016 8;18(8):823-32.). 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)
|
|
|
Pathogenic
(Oct 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Susceptibility to breast cancer
Pancreatic cancer susceptibility 3
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434917.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.2120delC (p.Pro707Leufs*2) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two patients … (more)
The c.2120delC (p.Pro707Leufs*2) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two patients affected with breast cancer (PMID 25575445, 26681312) and is extremely rare in general population databases. Therefore, this c.2120delC (p,Pro707Leus*2) variant in the PALB2 gene is classified as pathogenic. (less)
|
|
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Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202619.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(May 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601750.2
First in ClinVar: Oct 28, 2016 Last updated: Jan 01, 2022 |
|
|
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Pathogenic
(Oct 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489423.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(May 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149988.12
First in ClinVar: May 17, 2014 Last updated: Jun 10, 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 … (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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Nguyen-Dumont et al., 2015; Maxwell et al., 2016; Susswein et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25575445, 26681312, 27153395, 31447099, 29922827) (less)
|
|
|
Pathogenic
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019696.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000550717.10
First in ClinVar: Jan 06, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro707Leufs*2) 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.Pro707Leufs*2) 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 present in population databases (rs587780210, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and thyroid cancer and breast cancer (PMID: 25575445, 26681312). ClinVar contains an entry for this variant (Variation ID: 128128). For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
The c.2120delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2120, causing a translational frameshift with a predicted alternate stop codon (p.P707Lfs*2). This alteration was reported in a woman diagnosed with breast cancer at age 62 from a cohort of 1250 families enrolled in the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res.Treat. 2015 Jan;149(2):547-54). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med. 2016 8;18(8):823-32.). 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.
Comment:
The c.2120delC (p.Pro707Leufs*2) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two patients affected with breast cancer (PMID 25575445, 26681312) and is extremely rare in general population databases. Therefore, this c.2120delC (p,Pro707Leus*2) variant in the PALB2 gene is classified as pathogenic.
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 observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Nguyen-Dumont et al., 2015; Maxwell et al., 2016; Susswein et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25575445, 26681312, 27153395, 31447099, 29922827)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Pro707Leufs*2) 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 present in population databases (rs587780210, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and thyroid cancer and breast cancer (PMID: 25575445, 26681312). ClinVar contains an entry for this variant (Variation ID: 128128). For these reasons, this variant has been classified as Pathogenic.
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:
This variant deletes 1 nucleotide in exon 5 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 breast cancer, and in an individual affected with breast cancer and thyroid cancer (PMID: 25575445, 26681312; Color internal data). This variant has been identified in 2/251492 chromosomes 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:
The c.2120delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2120, causing a translational frameshift with a predicted alternate stop codon (p.P707Lfs*2). This alteration was reported in a woman diagnosed with breast cancer at age 62 from a cohort of 1250 families enrolled in the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res.Treat. 2015 Jan;149(2):547-54). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med. 2016 8;18(8):823-32.). 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.
Comment:
The c.2120delC (p.Pro707Leufs*2) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two patients affected with breast cancer (PMID 25575445, 26681312) and is extremely rare in general population databases. Therefore, this c.2120delC (p,Pro707Leus*2) variant in the PALB2 gene is classified as pathogenic.
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 observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Nguyen-Dumont et al., 2015; Maxwell et al., 2016; Susswein et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25575445, 26681312, 27153395, 31447099, 29922827)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Pro707Leufs*2) 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 present in population databases (rs587780210, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and thyroid cancer and breast cancer (PMID: 25575445, 26681312). ClinVar contains an entry for this variant (Variation ID: 128128). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| 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 |
| 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 rs587780210 ...
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.