ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4585G>A (p.Gly1529Arg)
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_000059.4(BRCA2):c.4585G>A (p.Gly1529Arg)
Variation ID: 37910 Accession: VCV000037910.56
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32338940 (GRCh38) [ NCBI UCSC ] 13: 32913077 (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 4, 2013 May 1, 2024 Aug 10, 2015 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.4585G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gly1529Arg missense NC_000013.11:g.32338940G>A NC_000013.10:g.32913077G>A NG_012772.3:g.28461G>A LRG_293:g.28461G>A LRG_293t1:c.4585G>A LRG_293p1:p.Gly1529Arg U43746.1:n.4813G>A - Protein change
- G1529R
- Other names
- p.G1529R:GGG>AGG
- 4813G>A
- Canonical SPDI
- NC_000013.11:32338939: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.
-
0.00060 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00039
Exome Aggregation Consortium (ExAC) 0.00042
Trans-Omics for Precision Medicine (TOPMed) 0.00043
The Genome Aggregation Database (gnomAD) 0.00044
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
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. |
|||
BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18723 | 18881 |
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. |
---|---|---|---|---|
Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000044446.29 | |
Benign (12) |
reviewed by expert panel
|
Aug 10, 2015 | RCV000113324.25 | |
Likely benign (2) |
criteria provided, single submitter
|
Apr 25, 2023 | RCV000148413.12 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
May 6, 2021 | RCV000162670.15 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Aug 15, 2023 | RCV000160225.35 | |
Likely benign (1) |
criteria provided, single submitter
|
Sep 23, 2019 | RCV000353459.13 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 14, 2023 | RCV000656605.25 | |
Benign (1) |
criteria provided, single submitter
|
Mar 14, 2019 | RCV003904874.1 |
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. |
|
---|---|---|---|---|---|
Benign
(Aug 10, 2015)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial 2
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000244450.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000000166 (less)
|
|
Uncertain significance
(Mar 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000538486.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.1%(42/66226) European; ClinVar: 8 B/LB (less)
Method: Genome/Exome Filtration
|
|
Benign
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744459.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
|
|
Likely benign
(Sep 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group D1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000383702.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(Sep 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000383703.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(Apr 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683634.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
Likely benign
(Sep 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602833.5
First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Oct 30, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000223766.1
First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
|
|
Likely benign
(Apr 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000267766.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Tissue: Blood
|
|
Likely benign
(Jun 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743301.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139093.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
Benign
(Aug 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001775532.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
|
|
Likely benign
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210607.11
First in ClinVar: Feb 24, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 19471317, 11447276, 11873550, 26332594, 28651617, 28324225, 24323938, 25896959, 20694749, 22811390, 24055113, 21520273, 25637381, 25782689, 23231788, 20104584, … (more)
This variant is associated with the following publications: (PMID: 19471317, 11447276, 11873550, 26332594, 28651617, 28324225, 24323938, 25896959, 20694749, 22811390, 24055113, 21520273, 25637381, 25782689, 23231788, 20104584, 23034506, 15983021, 10551859, 19747923, 12442171, 21990134, 27741520, 27153395, 27376475, 28283652, 17924331, 29356034, 32426482, 32846166) (less)
|
|
Likely benign
(May 06, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002533884.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
|
|
Benign
(Apr 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000494387.2
First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The variant of interest causes a missense change in a conserved position with 4/4 in silico programs predicting a "deleterious" outcome (SNPs&Go not … (more)
Variant summary: The variant of interest causes a missense change in a conserved position with 4/4 in silico programs predicting a "deleterious" outcome (SNPs&Go not captured here due to low reliability index). The variant of interest has an observed allele frequency of 57/121370 (1/2127) in controls, which does not significantly exceed the maximum expect allele frequency for a pathogenic BRCA2 variant, 1/1333. However, the variant of interest has been found in cases to co-occur with multiple potential pathogenic BRCA2 (1 - c.5350_5351delAA (p.Asn1784HisfsX2) and 1 - c.8755_10257del (p.Gly2919fsX15)) and BRCA1 (1 - c.3226A>T (p.Arg1076X)) variants including internal LCA sample that co-occurred with a BRCA1 variant, c.3358_3359delGT (p.Val1120X scored DV). Although, functional studies show no impairment on exon splicing but conflicting evidence for a role in homologous recombination via recruitment of RAD51, however, this functional analysis has not been indepdently reproduced by other laboratories and their relevance to in-vivo mechanisms of pathogenicity have not been unequivocally established. Furthermore, multiple reputable databases (ARUP, UMD, BIC, SCRP, GeneDx and Ambry Genetics) and publications (Easton_2007 and Lindor_2012) classify the variant as likely benign/benign/neutral. . Therefore, taken together, the variant of interest is classified as benign. (less)
|
|
Likely benign
(Apr 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004240315.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Benign
(Mar 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
BRCA2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004724366.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
Benign
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033244.5
First in ClinVar: Sep 16, 2023 Last updated: Apr 15, 2024 |
Comment:
BRCA2: BS1, BS2
Number of individuals with the variant: 3
|
|
Likely benign
(Oct 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002072432.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
Benign
(Apr 02, 2014)
|
criteria provided, single submitter
Method: literature only
|
Breast-ovarian cancer, familial 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000154094.2
First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022 |
|
|
Benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550337.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000072459.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
Likely Benign
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004845704.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 106
|
|
Benign
(Nov 19, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000213117.6
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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)
|
|
Benign
(Mar 02, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV004243636.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
Benign
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146453.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 12
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Austria
Observation 3:
Number of individuals with the variant: 5
Geographic origin: Western European
Observation 4:
Number of individuals with the variant: 2
Ethnicity/Population group: Ashkenazi
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Causian
Geographic origin: Germany
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: French Creole, Western European, African
Observation 8:
Number of individuals with the variant: 2
Ethnicity/Population group: Latin American, Caribbean
Observation 9:
Number of individuals with the variant: 2
Ethnicity/Population group: Native American
Observation 10:
Number of individuals with the variant: 42
Ethnicity/Population group: Western European
Observation 11:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Central/Eastern European, Italian
Observation 12:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, English
Observation 13:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Irish, German, French
Observation 14:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European, Latin American, Caribbe
Observation 15:
Number of individuals with the variant: 1
Ethnicity/Population group: Western Europeanan, Central/Eastern European
|
|
Benign
(Mar 01, 2011)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000054096.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
Likely benign
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Breast and/or ovarian cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190112.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
Likely benign
(Sep 11, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000787932.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV000591912.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Gly1529Arg variant was identified in 4 of 6448 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Borg 2010, Kauff 2008, … (more)
The BRCA2 p.Gly1529Arg variant was identified in 4 of 6448 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Borg 2010, Kauff 2008, Sinclair 2002). Two functional studies suggest that the variant affects binding with Rad51 (Chen 1999, Tal 2009), and one in silico study predicts that this variant may be deleterious using hierarchal modeling (Capanu 2011). However, there is conflicting evidence, two additional in silico studies using multifactorial-likelihood ratio models predict the variant to be neutral (Easton 2007, Lindor 2012). The variant was identified in dbSNP (ID: rs28897728) as “With Likely benign allele”, in Clinvitae database (classifications; benign and likely benign), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (classified as not pathogenic, of no clinical importance), COSMIC (in a medulloblastoma and endometrioid carcinoma), the ClinVar database (classification benign, reviewed by an expert panel, multiple submitters), GeneInsight COGR database (classifications of likely benign, benign, and uncertain significance by 4 clinical laboratories), the BIC database (75x with no clinical importance), and UMD (62x with a “neutral” classification, co-occurring with deleterious BRCA1, c.3226A>T, p.Arg1076X, BRCA2, c.5350_5351delAA, p.Asn1784HisfsX2, and BRCA2, c.8755_10257del, p.Gly2919fsx15 variants, increasing the likelihood that the p.Gly1529Arg variant does not have clinical significance. The variant was also identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), HAPMAP populations -EUR in 2 of 1006 chromosomes (frequency: 0.002) and AMR in 1 of 694 chromosomes (frequency: 0.0014), NHLBI GO Exome Sequencing Project in 6 of 8600 European American alleles (frequency: 0.0007), and the Exome Aggregation Consortium (March 14, 2016) in 51 of 120448 chromosomes (freq. 0.00042) in the following populations: European (Non-Finnish) in 42 of 66226 chromosomes (freq. 0.00063), South Asian in 6 of 16482 chromosomes (freq. 0.00036), Latino in 2 of 11536 chromosomes (freq. 0.00017), and other in 1 of 898 chromosomes (freq. 0.00011) but was not seen in African, East Asian, and Finnish populations. The p.Gly1529 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, Mutation Taster) suggest that the p.Gly1529Arg variant may impact the protein however this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905956.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958662.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Likely benign
(Oct 07, 2015)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778676.1
First in ClinVar: Jun 25, 2018 Last updated: Jun 25, 2018 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799991.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Functional assays for analysis of variants of uncertain significance in BRCA2. | Guidugli L | Human mutation | 2014 | PMID: 24323938 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling. | Moghadasi S | Journal of medical genetics | 2013 | PMID: 23231788 |
BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. | Pennington KP | Cancer | 2013 | PMID: 22811390 |
Effects of the missense mutations in canine BRCA2 on BRC repeat 3 functions and comparative analyses between canine and human BRC repeat 3. | Yoshikawa Y | PloS one | 2012 | PMID: 23071527 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. | Capanu M | Genetic epidemiology | 2011 | PMID: 21520273 |
Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 20927582 |
Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. | Cavallone L | Familial cancer | 2010 | PMID: 20694749 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Cancer-associated mutations in BRC domains of BRCA2 affect homologous recombination induced by Rad51. | Tal A | Journal of molecular biology | 2009 | PMID: 19747923 |
Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. | Caux-Moncoutier V | European journal of human genetics : EJHG | 2009 | PMID: 19471317 |
Assessment of functional effects of unclassified genetic variants. | Couch FJ | Human mutation | 2008 | PMID: 18951449 |
Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. | Lee E | Breast cancer research : BCR | 2008 | PMID: 18284688 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. | Haffty BG | Journal of medical genetics | 2006 | PMID: 15983021 |
Classification of Missense Mutations of Disease Genes. | Zhou X | Journal of the American Statistical Association | 2005 | PMID: 18418466 |
BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. | Pal T | Cancer | 2005 | PMID: 16284991 |
Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. | Weitzel JN | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2005 | PMID: 16030099 |
Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. | Adem C | Cancer | 2003 | PMID: 12491499 |
Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. | Pellegrini L | Nature | 2002 | PMID: 12442171 |
Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of the Department of Defense Familial Breast/Ovarian Cancer Research Project. | Fries MH | Military medicine | 2002 | PMID: 11873550 |
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. | Meindl A | International journal of cancer | 2002 | PMID: 11802209 |
Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. | Xia F | Proceedings of the National Academy of Sciences of the United States of America | 2001 | PMID: 11447276 |
Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control. | Chen CF | The Journal of biological chemistry | 1999 | PMID: 10551859 |
Kinetics of corneal transplant rejection in the rat penetrating keratoplasty model. | Holland EJ | Cornea | 1994 | PMID: 7924331 |
Plasma exchange-induced biological stress of the Hagemann-mediated systems: results of contact activation and plasma substitution. | Colla L | The International journal of artificial organs | 1985 | PMID: 4055113 |
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.4585G%3EA | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs28897728 ...
HelpRecord last updated May 08, 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.