ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3061G>A (p.Gly1021Arg)
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(7); 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.3061G>A (p.Gly1021Arg)
Variation ID: 230665 Accession: VCV000230665.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23621414 (GRCh38) [ NCBI UCSC ] 16: 23632735 (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 Dec 19, 2017 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.3061G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Gly1021Arg missense NC_000016.10:g.23621414C>T NC_000016.9:g.23632735C>T NG_007406.1:g.24944G>A LRG_308:g.24944G>A LRG_308t1:c.3061G>A LRG_308p1:p.Gly1021Arg - Protein change
- G1021R
- Other names
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- Canonical SPDI
- NC_000016.10:23621413:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
5906 | 5947 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 6, 2023 | RCV000214675.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 26, 2024 | RCV000558947.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2020 | RCV001798715.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 19, 2022 | RCV002265691.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 13, 2023 | RCV003328567.1 |
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
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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
(Oct 06, 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: SCV000274294.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.G1021R variant (also known as c.3061G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide … (more)
The p.G1021R variant (also known as c.3061G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3061. The glycine at codon 1021 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in 1/1240 probands from the Breast Cancer Family Registry who had previously screened negative for BRCA1 and BRCA2 mutations (Nguyen-Dumont T et al. Breast Cancer Res. Treat., 2015 Jan;149:547-54). This alteration was also found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 Mar;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785161.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Uncertain significance
(Jan 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043597.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Uncertain significance
(May 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547576.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: PALB2 c.3061G>A (p.Gly1021Arg) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of … (more)
Variant summary: PALB2 c.3061G>A (p.Gly1021Arg) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3061G>A has been reported in the literature in an individual (who was negative for BRCA1 and BRCA2 mutations) with a personal and/or family history of breast cancer (Nguyen-Dumont_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been found in an internal LCA sample (CHEK2 c.1100delC, (p.Thr367MetfsX15)), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated this missense change did not significantly affect PALB2 function in in a homology-directed DNA repair (HDR) assay (Wiltshire_2019). Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Likely benign
(Mar 30, 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019168.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Sep 13, 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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GeneDx
Accession: SCV004035894.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest an intermediate effect on homology-directed repair (HDR) activity (Wiltshire et al., 2020); Observed in individuals with a personal and family history suggestive of hereditary breast and ovarian cancer (Nguyen-Dumont et al., 2015; Gonzalez et al., 2022); This variant is associated with the following publications: (PMID: 25575445, 31636395, 33195396, 35610400) (less)
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Uncertain significance
(Jul 26, 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: SCV001735673.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 1021 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 1021 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). A functional study has shown the mutant protein to exhibit 80% of wild-type activity in a homology-directed repair assay (PMID: 31636395). This variant has been reported in an individual affected with pancreatic cancer (PMID: 33127389). This variant has been identified in 2/251450 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
(Jan 26, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633401.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1021 of the PALB2 protein (p.Gly1021Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1021 of the PALB2 protein (p.Gly1021Arg). This variant is present in population databases (rs143808171, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25575445, 35610400). ClinVar contains an entry for this variant (Variation ID: 230665). 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%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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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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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PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina. | Gonzalez A | Breast cancer research and treatment | 2022 | PMID: 35610400 |
PALB2 Variants: Protein Domains and Cancer Susceptibility. | Nepomuceno TC | Trends in cancer | 2021 | PMID: 33139182 |
Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017. | Ding D | Cancer letters | 2021 | PMID: 33127389 |
Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction. | Boonen RACM | Frontiers in molecular biosciences | 2020 | PMID: 33195396 |
Functional characterization of 84 PALB2 variants of uncertain significance. | Wiltshire T | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31636395 |
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 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Text-mined citations for rs143808171 ...
HelpRecord 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.