Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate BRCA2 interaction and PARP inhibitor response to be comparable to wild type (Rodrigue 2019); Observed in an individual with a personal or family history of breast cancer (Blanco 2012); This variant is associated with the following publications: (PMID: 31586400, 22052327, 33195396)
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.620C>G (p.Pro207Arg)
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.
(6)
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.
Uncertain significance
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.620C>G (p.Pro207Arg)
Variation ID: 126760 Accession: VCV000126760.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23635926 (GRCh38) [ NCBI UCSC ] 16: 23647247 (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 Apr 19, 2014 May 1, 2024 Nov 5, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.620C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Pro207Arg missense NC_000016.10:g.23635926G>C NC_000016.9:g.23647247G>C NG_007406.1:g.10432C>G LRG_308:g.10432C>G LRG_308t1:c.620C>G LRG_308p1:p.Pro207Arg - Protein change
- P207R
- Other names
- -
- Canonical SPDI
- NC_000016.10:23635925:G:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 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 |
5913 | 5955 | |
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 (2) |
criteria provided, single submitter
|
Nov 5, 2023 | RCV000114649.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2023 | RCV000776330.8 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2022 | RCV001572249.5 |
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
(Mar 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001796857.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate BRCA2 interaction and PARP inhibitor response to be comparable to wild type (Rodrigue 2019); Observed in an individual with a personal or family history of breast cancer (Blanco 2012); This variant is associated with the following publications: (PMID: 31586400, 22052327, 33195396) (less)
|
|
|
Uncertain significance
(Jan 25, 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: SCV000911675.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with arginine at codon 207 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with arginine at codon 207 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 reported in a family affected with breast and/or ovarian cancer (PMID: 22052327) and in an unaffected control individual in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 1/251410 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
(Nov 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260710.7
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 207 of the PALB2 protein (p.Pro207Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 207 of the PALB2 protein (p.Pro207Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 22052327). ClinVar contains an entry for this variant (Variation ID: 126760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222352.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000004 (1/251410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000004 (1/251410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer, including male breast cancer (PMID: 22052327 (2012)). An experimental study reports this variant does not significantly affect PALB2 protein function, however further studies are needed to determine an overall impact (PMID: 31586400 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001187120.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.P207R variant (also known as c.620C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide … (more)
The p.P207R variant (also known as c.620C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 620. The proline at codon 207 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in 1/131 BRCA1/2 negative individuals with a personal and/or family history suggestive of hereditary breast cancer, including at least one case of male breast cancer (Blanco A et al. Breast Cancer Res. Treat., 2012 Feb;132:307-15). This alteration was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a BRCA1 binding assay, this alteration was found to have intermediate activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is not 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)
|
|
|
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: SCV001192993.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
|
Comment:
Comment:
This missense variant replaces proline with arginine at codon 207 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 reported in a family affected with breast and/or ovarian cancer (PMID: 22052327) and in an unaffected control individual in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 1/251410 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.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 207 of the PALB2 protein (p.Pro207Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 22052327). ClinVar contains an entry for this variant (Variation ID: 126760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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:
The frequency of this variant in the general population, 0.000004 (1/251410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer, including male breast cancer (PMID: 22052327 (2012)). An experimental study reports this variant does not significantly affect PALB2 protein function, however further studies are needed to determine an overall impact (PMID: 31586400 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The p.P207R variant (also known as c.620C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 620. The proline at codon 207 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in 1/131 BRCA1/2 negative individuals with a personal and/or family history suggestive of hereditary breast cancer, including at least one case of male breast cancer (Blanco A et al. Breast Cancer Res. Treat., 2012 Feb;132:307-15). This alteration was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a BRCA1 binding assay, this alteration was found to have intermediate activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is not 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.
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 at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate BRCA2 interaction and PARP inhibitor response to be comparable to wild type (Rodrigue 2019); Observed in an individual with a personal or family history of breast cancer (Blanco 2012); This variant is associated with the following publications: (PMID: 31586400, 22052327, 33195396)
Comment:
This missense variant replaces proline with arginine at codon 207 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 reported in a family affected with breast and/or ovarian cancer (PMID: 22052327) and in an unaffected control individual in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 1/251410 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.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 207 of the PALB2 protein (p.Pro207Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 22052327). ClinVar contains an entry for this variant (Variation ID: 126760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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:
The frequency of this variant in the general population, 0.000004 (1/251410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer, including male breast cancer (PMID: 22052327 (2012)). An experimental study reports this variant does not significantly affect PALB2 protein function, however further studies are needed to determine an overall impact (PMID: 31586400 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The p.P207R variant (also known as c.620C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 620. The proline at codon 207 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in 1/131 BRCA1/2 negative individuals with a personal and/or family history suggestive of hereditary breast cancer, including at least one case of male breast cancer (Blanco A et al. Breast Cancer Res. Treat., 2012 Feb;132:307-15). This alteration was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a BRCA1 binding assay, this alteration was found to have intermediate activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is not 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.
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 |
| A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor. | Rodrigue A | Nucleic acids research | 2019 | PMID: 31586400 |
| Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer. | Blanco A | Breast cancer research and treatment | 2012 | PMID: 22052327 |
Text-mined citations for rs515726125 ...
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.