Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Casadei 2011, Decker 2017); This variant is associated with the following publications: (PMID: 21285249, 28024868, 28779002, 31843900)
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser)
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.
(11)
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.
Conflicting classifications of pathogenicity
Uncertain significance(7); Likely benign(1)
Uncertain significance(7); Likely benign(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser)
Variation ID: 126679 Accession: VCV000126679.30
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23624091 (GRCh38) [ NCBI UCSC ] 16: 23635412 (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 Oct 11, 2015 Jun 17, 2024 Mar 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.2752C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Pro918Ser missense NC_000016.10:g.23624091G>A NC_000016.9:g.23635412G>A NG_007406.1:g.22267C>T LRG_308:g.22267C>T LRG_308t1:c.2752C>T LRG_308p1:p.Pro918Ser - Protein change
- P918S
- Other names
- -
- Canonical SPDI
- NC_000016.10:23624090: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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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 |
5923 | 5965 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Mar 3, 2024 | RCV000114556.22 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 8, 2023 | RCV000165106.15 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2021 | RCV000478088.6 | |
| Benign (1) |
no assertion criteria provided
|
Sep 1, 2019 | RCV001171432.4 |
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 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566460.5
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in … (more)
Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Casadei 2011, Decker 2017); This variant is associated with the following publications: (PMID: 21285249, 28024868, 28779002, 31843900) (less)
|
|
|
Uncertain significance
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000255090.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21285249; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
(Nov 08, 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: SCV000685974.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An RNA study has reported that this variant does not impact mRNA splicing (PMID: 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer (PMID: 21285249, 28779002, 29522266) and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010192). This variant has not been identified 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
(Oct 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469848.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
|
Uncertain significance
(Dec 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488007.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Likely benign
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019665.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical … (more)
This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. (less)
|
|
|
Uncertain significance
(Mar 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215816.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide … (more)
The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide position 2752. The proline at codon 918 is replaced by serine, an amino acid with similar properties. This alteration was reported in 4/1144 BRCA1/2 negative breast cancer patients with at least two relatives diagnosed with breast cancer (Casadei S et al. Cancer Res., 2011 Mar;71:2222-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). Additionally, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). 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)
|
|
|
Uncertain significance
(Mar 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202116.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Benign
(Sep 01, 2019)
|
no assertion criteria provided
Method: research
|
not specified
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251342.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
|
|
|
|
Uncertain significance
(Jul 13, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000886698.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
|
|
|
Uncertain significance
(May 13, 2019)
|
no assertion criteria provided
Method: curation
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193284.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21285249; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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:
This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An RNA study has reported that this variant does not impact mRNA splicing (PMID: 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer (PMID: 21285249, 28779002, 29522266) and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010192). This variant has not been identified 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:
This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Comment:
The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide position 2752. The proline at codon 918 is replaced by serine, an amino acid with similar properties. This alteration was reported in 4/1144 BRCA1/2 negative breast cancer patients with at least two relatives diagnosed with breast cancer (Casadei S et al. Cancer Res., 2011 Mar;71:2222-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). Additionally, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). 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.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
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:
Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Casadei 2011, Decker 2017); This variant is associated with the following publications: (PMID: 21285249, 28024868, 28779002, 31843900)
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21285249; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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:
This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An RNA study has reported that this variant does not impact mRNA splicing (PMID: 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer (PMID: 21285249, 28779002, 29522266) and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010192). This variant has not been identified 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:
This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Comment:
The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide position 2752. The proline at codon 918 is replaced by serine, an amino acid with similar properties. This alteration was reported in 4/1144 BRCA1/2 negative breast cancer patients with at least two relatives diagnosed with breast cancer (Casadei S et al. Cancer Res., 2011 Mar;71:2222-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). Additionally, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). 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.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
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 |
| Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
| Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. | Abe T | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30883245 |
| 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 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. | Casadei S | Cancer research | 2011 | PMID: 21285249 |
Text-mined citations for rs515726094 ...
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 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.