Variant summary: PALB2 c.2474G>C (p.Arg825Thr) 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 0.00016 in 251430 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 14.079 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2474G>C has been reported in the literature in individuals affected with various types of cancers includin leiomyosarcoma, stomach adenocarcinoma, breast cancer and urothelial carcinoma, all without strong evidence for causality (Yang_2015, Lu_2015, Kwong_2020, Xie_2018, Yang_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; four classified as VUS while four classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2474G>C (p.Arg825Thr)
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(3); Likely benign(8)
Uncertain significance(3); Likely benign(8)
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.2474G>C (p.Arg825Thr)
Variation ID: 185630 Accession: VCV000185630.54
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23629680 (GRCh38) [ NCBI UCSC ] 16: 23641001 (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 9, 2016 Oct 20, 2024 Jan 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.2474G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Arg825Thr missense NC_000016.10:g.23629680C>G NC_000016.9:g.23641001C>G NG_007406.1:g.16678G>C LRG_308:g.16678G>C LRG_308t1:c.2474G>C LRG_308p1:p.Arg825Thr - Protein change
- R825T
- Other names
- -
- Canonical SPDI
- NC_000016.10:23629679:C:G
-
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.
-
0.00080 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00014
The Genome Aggregation Database (gnomAD), exomes 0.00016
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00008
- 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 |
5921 | 5963 | |
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 (4) |
criteria provided, conflicting classifications
|
Feb 3, 2021 | RCV000165079.15 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Aug 3, 2023 | RCV000236812.36 | |
| Likely benign (1) |
criteria provided, single submitter
|
Aug 23, 2021 | RCV000780569.4 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV001086620.10 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jul 20, 2020 | RCV001256975.3 |
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
(Jan 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000747823.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Likely benign
(Feb 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685952.3
First in ClinVar: Feb 19, 2018 Last updated: Mar 25, 2020 |
|
|
|
Likely benign
(Aug 23, 2021)
|
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: SCV000917957.2
First in ClinVar: Jun 02, 2019 Last updated: Sep 08, 2021 |
Comment:
Variant summary: PALB2 c.2474G>C (p.Arg825Thr) 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.2474G>C (p.Arg825Thr) 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 0.00016 in 251430 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 14.079 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2474G>C has been reported in the literature in individuals affected with various types of cancers includin leiomyosarcoma, stomach adenocarcinoma, breast cancer and urothelial carcinoma, all without strong evidence for causality (Yang_2015, Lu_2015, Kwong_2020, Xie_2018, Yang_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; four classified as VUS while four classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046489.2
First in ClinVar: Jan 01, 2022 Last updated: Jan 06, 2024 |
|
|
|
Likely benign
(Apr 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215782.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Jun 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000807088.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
|
Likely benign
(Jul 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
ACT Genomics,
Accession: SCV001424575.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
The allele frequency of this variant c.2474G>C (p.Arg825Thr) is 0.0037 in East Asian of gnomAD and 0.004 in East Asian of 1000 Genomes, which is … (more)
The allele frequency of this variant c.2474G>C (p.Arg825Thr) is 0.0037 in East Asian of gnomAD and 0.004 in East Asian of 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between arginine and threonine. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign. (less)
Sex: female
Geographic origin: Taiwan, East Asia
|
|
|
Likely benign
(Feb 03, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530700.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Dec 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292657.13
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 28580595, 26692951)
|
|
|
Likely benign
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253594.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245837.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
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Comment:
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
The allele frequency of this variant c.2474G>C (p.Arg825Thr) is 0.0037 in East Asian of gnomAD and 0.004 in East Asian of 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between arginine and threonine. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign.
Comment:
This variant is associated with the following publications: (PMID: 28580595, 26692951)
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:
Variant summary: PALB2 c.2474G>C (p.Arg825Thr) 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 0.00016 in 251430 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 14.079 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2474G>C has been reported in the literature in individuals affected with various types of cancers includin leiomyosarcoma, stomach adenocarcinoma, breast cancer and urothelial carcinoma, all without strong evidence for causality (Yang_2015, Lu_2015, Kwong_2020, Xie_2018, Yang_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; four classified as VUS while four classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
The allele frequency of this variant c.2474G>C (p.Arg825Thr) is 0.0037 in East Asian of gnomAD and 0.004 in East Asian of 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between arginine and threonine. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign.
Comment:
This variant is associated with the following publications: (PMID: 28580595, 26692951)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic characteristics of two breast malignant phyllodes tumors during pregnancy and lactation identified through whole-exome sequencing. | Lei T | Orphanet journal of rare diseases | 2022 | PMID: 36271373 |
| Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel. | Jiang W | Journal of medical genetics | 2022 | PMID: 33563768 |
| Genomic profiling of Chinese patients with urothelial carcinoma. | Yang B | BMC cancer | 2021 | PMID: 33588785 |
| 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 |
| Clinical and Genetic Analysis of CHD7 Expands the Genotype and Phenotype of CHARGE Syndrome. | Qin Z | Frontiers in genetics | 2020 | PMID: 32625235 |
| Comparison of BRCA versus non-BRCA germline mutations and associated somatic mutation profiles in patients with unselected breast cancer. | Chen B | Aging | 2020 | PMID: 32091409 |
| Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel. | Kwong A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32068069 |
| Metastatic Adrenocortical Carcinoma: a Single Institutional Experience. | Owen DH | Hormones & cancer | 2019 | PMID: 31468469 |
| Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. | Xie Y | Clinical genetics | 2018 | PMID: 28580595 |
| Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma. | Yang CY | American journal of translational research | 2015 | PMID: 26692951 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
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Text-mined citations for rs146218439 ...
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 Oct 20, 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.