ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2435C>T (p.Pro812Leu)
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
-
NM_024675.4(PALB2):c.2435C>T (p.Pro812Leu)
Variation ID: 246424 Accession: VCV000246424.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23629719 (GRCh38) [ NCBI UCSC ] 16: 23641040 (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 Jul 25, 2016 Feb 20, 2024 Jan 8, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024675.4:c.2435C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Pro812Leu missense NC_000016.10:g.23629719G>A NC_000016.9:g.23641040G>A NG_007406.1:g.16639C>T LRG_308:g.16639C>T LRG_308t1:c.2435C>T LRG_308p1:p.Pro812Leu - Protein change
- P812L
- Other names
- -
- Canonical SPDI
- NC_000016.10:23629718:G:A
-
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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
5759 | 5798 |
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 (1) |
criteria provided, single submitter
|
Aug 1, 2022 | RCV000235316.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000635929.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2022 | RCV000575251.8 | |
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001357974.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 14, 2023 | RCV003330604.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 30, 2021 | RCV002494681.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(May 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000665117.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.P812L variant (also known as c.2435C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide … (more)
The p.P812L variant (also known as c.2435C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2435. The proline at codon 812 is replaced by leucine, an amino acid with similar properties. This variant was reported in 6/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been detected in a Serbian female with ovarian cancer (Krivokuca A et al. J Hum Genet, 2019 Apr;64:281-290). This amino acid position is 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)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Aug 30, 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: SCV002784267.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000293974.13
First in ClinVar: Jul 25, 2016 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24485656, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24485656, 30455982, 30651582, 26689913) (less)
|
|
Uncertain significance
(Aug 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039491.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: PALB2 c.2435C>T (p.Pro812Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PALB2 c.2435C>T (p.Pro812Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2435C>T has been reported in the literature in individuals affected with childhood tumors (e.g. Chan_2018) and ovarian cancer (e.g. Lu_2015, Krivokuca_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30455982, 30651582, 26689913). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Oct 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202010.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Aug 29, 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: SCV000911845.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with leucine at codon 812 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with leucine at codon 812 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 detected in a breast cancer case-control meta-analysis in 6/60466 cases and 7/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010898) and in an individual affected with ovarian cancer (PMID: 30651582). This variant has been identified in 6/251488 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
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000757356.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 812 of the PALB2 protein (p.Pro812Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 812 of the PALB2 protein (p.Pro812Leu). This variant is present in population databases (rs774502617, gnomAD 0.03%). This missense change has been observed in individual(s) with PALB2-related conditions (PMID: 26689913, 30651582). ClinVar contains an entry for this variant (Variation ID: 246424). 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
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553589.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Pro812Leu variant was identified in 1 of 204 proband chromosomes (frequency: 0.005) from an Asian individual with an unspecified childhood tumor (Chan 2018). … (more)
The PALB2 p.Pro812Leu variant was identified in 1 of 204 proband chromosomes (frequency: 0.005) from an Asian individual with an unspecified childhood tumor (Chan 2018). The variant was also identified in dbSNP (ID: rs774502617) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, and Invitae). The variant was not identified in the LOVD 3.0 database. The variant was identified in control databases in 6 of 246272 chromosomes at a frequency of 0.000024 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 111720 chromosomes (freq: 0.000009), East Asian in 5 of 17248 chromosomes (freq: 0.0003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Pro812 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
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 |
---|---|---|---|---|
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 |
Germline mutations in cancer susceptibility genes in high grade serous ovarian cancer in Serbia. | Krivokuca A | Journal of human genetics | 2019 | PMID: 30651582 |
Clinical relevance of screening checklists for detecting cancer predisposition syndromes in Asian childhood tumours. | Chan SH | NPJ genomic medicine | 2018 | PMID: 30455982 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Text-mined citations for rs774502617 ...
HelpRecord last updated Feb 28, 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.