ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.48G>A (p.Lys16=)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.48G>A (p.Lys16=)
Variation ID: 143978 Accession: VCV000143978.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23641110 (GRCh38) [ NCBI UCSC ] 16: 23652431 (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 Aug 24, 2014 May 1, 2024 Sep 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.48G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Lys16= synonymous NC_000016.10:g.23641110C>T NC_000016.9:g.23652431C>T NG_007406.1:g.5248G>A LRG_308:g.5248G>A LRG_308t1:c.48G>A LRG_308p1:p.Lys16= - Protein change
- Other names
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- Canonical SPDI
- NC_000016.10:23641109: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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
5899 | 5940 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Pathogenic (1) |
no assertion criteria provided
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- | RCV000133492.2 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV001030105.9 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2019 | RCV000566830.8 |
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
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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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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499698.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Likely pathogenic
(Nov 27, 2019)
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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: SCV001354215.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant causes a G>A nucleotide substitution at the last position of exon 1 of the PALB2 gene. Splice site prediction tools suggest that this … (more)
This variant causes a G>A nucleotide substitution at the last position of exon 1 of the PALB2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes loss of the canonical donor site of intron 1, resulting in use of an upstream cryptic donor site and a transcript that lacks 17 nucleotides at the 3′ end of exon 1. At the protein level this is expected to result in a frameshift and loss of protein function (p.Cys11fs). This variant has been reported in an individual affected with hereditary breast cancer in the literature (PMID 24556926, 25099575). 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. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Sep 26, 2022)
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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: SCV001229787.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 16 of the PALB2 mRNA. It is a 'silent' … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 16 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant has been observed in individual(s) with breast cancer (PMID: 24556926). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 24556926; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 143978). (less)
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Likely pathogenic
(Sep 15, 2017)
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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: SCV000665419.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.48G>A variant (also known as p.K16K), located in coding exon 1 of the PALB2 gene, results from a G to A substitution at nucleotide … (more)
The c.48G>A variant (also known as p.K16K), located in coding exon 1 of the PALB2 gene, results from a G to A substitution at nucleotide position 48. This nucleotide substitution does not change the amino acid at codon 16. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In one assay using lymphoblastoid cell lines from a patient with the c.48G>A alteration, the canonical donor splice site was abolished and an alternative splice site was used resulting in an aberrant transcript and a premature termination codon. The aberrant transcript was not present in one control, and reportedly absent in additional controls from individuals with mutations in other genes and from blood donors (Catucci I et al. Genet. Med. 2014 Sep;16:688-94). In addition, this alteration has been reported in patients with familial breast cancer (Catucci I et al. Genet. Med. 2014 Sep;16:688-94; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188435.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 24556926].
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
germline
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SNPedia
Accession: SCV000188566.1
First in ClinVar: Aug 24, 2014 Last updated: Aug 24, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(May 13, 2019)
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no assertion criteria provided
Method: curation
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001192905.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
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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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Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. | Catucci I | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24556926 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs587776405 ...
HelpRecord last updated Jun 23, 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.