ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2821A>G (p.Ile941Val)
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.
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.2821A>G (p.Ile941Val)
Variation ID: 460961 Accession: VCV000460961.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23624022 (GRCh38) [ NCBI UCSC ] 16: 23635343 (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 Feb 19, 2018 Aug 4, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.2821A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Ile941Val missense NC_000016.10:g.23624022T>C NC_000016.9:g.23635343T>C NG_007406.1:g.22336A>G LRG_308:g.22336A>G LRG_308t1:c.2821A>G LRG_308p1:p.Ile941Val - Protein change
- I941V
- Other names
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- Canonical SPDI
- NC_000016.10:23624021:T:C
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
5862 | 5903 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV000534984.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 8, 2023 | RCV000572648.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 1, 2023 | RCV000759902.12 | |
Hereditary breast cancer
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Uncertain significance (1) |
no assertion criteria provided
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Apr 8, 2020 | RCV001005026.4 |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 12, 2022 | RCV002490998.1 |
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
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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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Uncertain significance
(May 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889588.2
First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022 |
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Uncertain significance
(Feb 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807001.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002044263.3
First in ClinVar: Jan 01, 2022 Last updated: Mar 04, 2023 |
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, or colon cancer (Zidan et al., 2017; Moradian et al., 2021); This variant is associated with the following publications: (PMID: 28828701, 33558524, 28873162, 19609323, 20871615, 24485656) (less)
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Uncertain significance
(Mar 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000685983.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces isoleucine with valine at codon 941 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces isoleucine with valine at codon 941 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 observed in an individual affected with bilateral breast cancer with positive family history of breast cancer (PMID: 33558524), as well as in two individuals affected with breast cancer in a case-control study (PMID: 33471991). This variant has been identified in 5/250838 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)
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Uncertain significance
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000633379.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 941 of the PALB2 protein (p.Ile941Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 941 of the PALB2 protein (p.Ile941Val). This variant is present in population databases (rs778602038, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28828701, 33558524). ClinVar contains an entry for this variant (Variation ID: 460961). 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 expected to disrupt PALB2 protein function with a positive 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)
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Uncertain significance
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000663316.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.I941V variant (also known as c.2821A>G), located in coding exon 8 of the PALB2 gene, results from an A to G substitution at nucleotide … (more)
The p.I941V variant (also known as c.2821A>G), located in coding exon 8 of the PALB2 gene, results from an A to G substitution at nucleotide position 2821. The isoleucine at codon 941 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in different cancer cohorts and in controls (Mandelker D. et al. JAMA. 2017;318(9):825-835; Hauke J. et al. Cancer Med. 2018;7(4):1349-1358; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This alteration was also identified in 1/68 non-Jewish Israeli individuals determined to be at high-risk for breast/ovarian cancer (Zidan J et al. Breast Cancer Res Treat, 2017 Dec;166:881-885).This amino acid position is highly 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)
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Likely benign
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004698357.6
First in ClinVar: Mar 10, 2024 Last updated: Aug 04, 2024 |
Comment:
PALB2: BP4
Number of individuals with the variant: 1
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Uncertain significance
(Apr 08, 2020)
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no assertion criteria provided
Method: research
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Hereditary breast cancer
Affected status: yes
Allele origin:
germline
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Center of Medical Genetics and Primary Health Care
Accession: SCV000987280.2
First in ClinVar: Mar 04, 2020 Last updated: Apr 22, 2020 |
Comment:
ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: WD40 repeat-like (V872-1185 aa) domain, which serves as platform for the assembly of protein complexes (e.g., BRCA1 / … (more)
ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: WD40 repeat-like (V872-1185 aa) domain, which serves as platform for the assembly of protein complexes (e.g., BRCA1 / RAD51) or mediators of transient interplay among other proteins. Hot spot has 283 non-VUS coding variants (146 pathogenic and 137 benign), pathogenicity = 51.6% > threshold 17.2%. PM2 Pathogenic Moderate: GnomAD exomes allele frequency = 0.0000199 < 0.0001 threshold for recessive gene PALB2. Variant not found in GnomAD genomes. PP3 Pathogenic Supporting: 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, SIFT, PolyPhen-2, Align-GVGD vs 5 benign predictions from DEOGEN2, M-CAP, MVP, PrimateAI and REVEL. PP4 Pathogenic Supporting: Female patient was diagnosed with bilateral breast cancer at the age of 55 y.o. with strong family history of breast cancer. 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)
Age: 50-59 years
Sex: female
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer. | Moradian MM | Human genome variation | 2021 | PMID: 33558524 |
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 |
Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. | Weitzel JN | Cancer | 2019 | PMID: 31206626 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Inherited predisposition to breast and ovarian cancer in non-Jewish populations in Israel. | Zidan J | Breast cancer research and treatment | 2017 | PMID: 28828701 |
Text-mined citations for rs778602038 ...
HelpRecord last updated Aug 04, 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.