Variant summary: PALB2 c.3469C>T (p.Gln1157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein disrupting Partner and localiser of BRCA2, WD40 domain, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr1183X). The variant was absent in 251476 control chromosomes. To our knowledge, no occurrence of c.3469C>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3469C>T (p.Gln1157Ter)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.3469C>T (p.Gln1157Ter)
Variation ID: 823806 Accession: VCV000823806.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23603551 (GRCh38) [ NCBI UCSC ] 16: 23614872 (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 16, 2020 May 1, 2024 Dec 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.3469C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Gln1157Ter nonsense NC_000016.10:g.23603551G>A NC_000016.9:g.23614872G>A NG_007406.1:g.42807C>T LRG_308:g.42807C>T LRG_308t1:c.3469C>T - Protein change
- Q1157*
- Other names
- -
- Canonical SPDI
- NC_000016.10:23603550:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
5910 | 5952 | |
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
|
Mar 9, 2023 | RCV001020375.6 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 14, 2023 | RCV001860983.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2023 | RCV003226417.1 |
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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Likely pathogenic
(Mar 13, 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: SCV003923192.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: PALB2 c.3469C>T (p.Gln1157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein disrupting Partner and localiser of … (more)
Variant summary: PALB2 c.3469C>T (p.Gln1157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein disrupting Partner and localiser of BRCA2, WD40 domain, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr1183X). The variant was absent in 251476 control chromosomes. To our knowledge, no occurrence of c.3469C>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001181848.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.Q1157* pathogenic mutation (also known as c.3469C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at … (more)
The p.Q1157* pathogenic mutation (also known as c.3469C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3469. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Sep 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004189340.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 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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Likely pathogenic
(Apr 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202745.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Jan 25, 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: SCV004357804.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. This variant … (more)
This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the BRCA2 and RAD51 binding domains which have been reported to be essential in the homology directed repair pathway. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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)
|
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002227067.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1157*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gln1157*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 823806). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
The p.Q1157* pathogenic mutation (also known as c.3469C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3469. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the BRCA2 and RAD51 binding domains which have been reported to be essential in the homology directed repair pathway. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.Gln1157*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 823806). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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:
Variant summary: PALB2 c.3469C>T (p.Gln1157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein disrupting Partner and localiser of BRCA2, WD40 domain, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr1183X). The variant was absent in 251476 control chromosomes. To our knowledge, no occurrence of c.3469C>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The p.Q1157* pathogenic mutation (also known as c.3469C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3469. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the BRCA2 and RAD51 binding domains which have been reported to be essential in the homology directed repair pathway. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.Gln1157*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 823806). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
| Rare germline mutations in PALB2 and breast cancer risk: a population-based study. | Tischkowitz M | Human mutation | 2012 | PMID: 22241545 |
| PALB2 mutations in familial breast and pancreatic cancer. | Hofstatter EW | Familial cancer | 2011 | PMID: 21365267 |
| Structural basis for recruitment of BRCA2 by PALB2. | Oliver AW | EMBO reports | 2009 | PMID: 19609323 |
| 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 rs1597062038 ...
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.