This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2773G>C (p.Val925Leu)
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.
(14)
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.
Uncertain significance
14
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.2773G>C (p.Val925Leu)
Variation ID: 126681 Accession: VCV000126681.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23624070 (GRCh38) [ NCBI UCSC ] 16: 23635391 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.2773G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Val925Leu missense NC_000016.10:g.23624070C>G NC_000016.9:g.23635391C>G NG_007406.1:g.22288G>C LRG_308:g.22288G>C LRG_308t1:c.2773G>C LRG_308p1:p.Val925Leu - Protein change
- V925L
- Other names
- -
- Canonical SPDI
- NC_000016.10:23624069:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 |
5913 | 5955 | |
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. |
|---|---|---|---|---|
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 14, 2024 | RCV000114558.28 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 5, 2023 | RCV000129279.19 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Aug 18, 2021 | RCV000764047.11 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000235847.20 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 23, 2023 | RCV001798299.11 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579147.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM2_SUP, BP4
|
Number of individuals with the variant: 2
Sex: female
|
|
|
Uncertain significance
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043596.2
First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000259312.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202089.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Feb 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292755.15
First in ClinVar: Jul 24, 2016 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, prostate, or colon cancer (PMID: 18288683, 19763884, 27153395, 28944238, 29052111); This variant is associated with the following publications: (PMID: 18288683, 19763884, 26635394, 29052111, 27153395, 24485656, 19609323, 20871615, 17420451, 28944238) (less)
|
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000895001.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Uncertain significance
(Oct 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489581.2
First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Aug 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611497.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019621.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
|
Uncertain significance
(Jun 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902881.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with leucine at codon 925 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with leucine at codon 925 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and prostate cancer in the literature (PMID: 18288683, 19763884, 29052111, 29522266) and in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010124). This variant has been identified in 4/245296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184039.11
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide … (more)
The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide position 2773. The valine at codon 925 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 95 prostate cancer families and thought unlikely to be pathogenic by authors (Tischkowitz M et al. Prostate. 2008 May;68(6):675-8). This variant was also identified in a patient with colorectal cancer who met Amsterdam criteria whose tumor was mismatch repair proficient (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another study detected this alteration in 1/338 breast cancer patients and 0/89 ovarian cancer patients from Poland and Ukraine (Myszka A et al. Fam. Cancer. 2018 07;17:345-349). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Sep 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197076.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Uncertain significance
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005331341.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Sep 30, 2019)
|
no assertion criteria provided
Method: curation
|
not provided
Affected status: no
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193286.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke.
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, prostate, or colon cancer (PMID: 18288683, 19763884, 27153395, 28944238, 29052111); This variant is associated with the following publications: (PMID: 18288683, 19763884, 26635394, 29052111, 27153395, 24485656, 19609323, 20871615, 17420451, 28944238)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
This missense variant replaces valine with leucine at codon 925 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and prostate cancer in the literature (PMID: 18288683, 19763884, 29052111, 29522266) and in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010124). This variant has been identified in 4/245296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide position 2773. The valine at codon 925 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 95 prostate cancer families and thought unlikely to be pathogenic by authors (Tischkowitz M et al. Prostate. 2008 May;68(6):675-8). This variant was also identified in a patient with colorectal cancer who met Amsterdam criteria whose tumor was mismatch repair proficient (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another study detected this alteration in 1/338 breast cancer patients and 0/89 ovarian cancer patients from Poland and Ukraine (Myszka A et al. Fam. Cancer. 2018 07;17:345-349). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke.
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 sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, prostate, or colon cancer (PMID: 18288683, 19763884, 27153395, 28944238, 29052111); This variant is associated with the following publications: (PMID: 18288683, 19763884, 26635394, 29052111, 27153395, 24485656, 19609323, 20871615, 17420451, 28944238)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
This missense variant replaces valine with leucine at codon 925 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and prostate cancer in the literature (PMID: 18288683, 19763884, 29052111, 29522266) and in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010124). This variant has been identified in 4/245296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide position 2773. The valine at codon 925 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 95 prostate cancer families and thought unlikely to be pathogenic by authors (Tischkowitz M et al. Prostate. 2008 May;68(6):675-8). This variant was also identified in a patient with colorectal cancer who met Amsterdam criteria whose tumor was mismatch repair proficient (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another study detected this alteration in 1/338 breast cancer patients and 0/89 ovarian cancer patients from Poland and Ukraine (Myszka A et al. Fam. Cancer. 2018 07;17:345-349). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
| Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine. | Myszka A | Familial cancer | 2018 | PMID: 29052111 |
| Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
| 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 |
| RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins. | Mao F | Nucleic acids research | 2016 | PMID: 26635394 |
| A PALB2 germline mutation associated with hereditary breast cancer in Italy. | Papi L | Familial cancer | 2010 | PMID: 19763884 |
| Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer. | Tischkowitz M | The Prostate | 2008 | PMID: 18288683 |
| Analysis of PALB2/FANCN-associated breast cancer families. | Tischkowitz M | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17420451 |
Text-mined citations for rs180177125 ...
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 10, 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.