ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8182G>A (p.Val2728Ile)
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.8182G>A (p.Val2728Ile)
Variation ID: 41565 Accession: VCV000041565.88
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32363384 (GRCh38) [ NCBI UCSC ] 13: 32937521 (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 12, 2013 May 1, 2024 Jun 18, 2019 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.8182G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Val2728Ile missense NC_000013.11:g.32363384G>A NC_000013.10:g.32937521G>A NG_012772.3:g.52905G>A LRG_293:g.52905G>A LRG_293t1:c.8182G>A LRG_293p1:p.Val2728Ile NP_000050.2:p.Val2728Ile U43746.1:n.8410G>A - Protein change
- V2728I
- Other names
- p.V2728I:GTT>ATT
- NP_000050.3:p.Val2728Ile
- Canonical SPDI
- NC_000013.11:32363383: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.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00239
Trans-Omics for Precision Medicine (TOPMed) 0.00244
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00331
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 | ||
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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/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000034462.47 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000045443.28 | |
Benign (11) |
reviewed by expert panel
|
Jun 18, 2019 | RCV000113882.26 | |
Benign/Likely benign (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000120362.38 | |
Likely benign (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148414.11 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2022 | RCV000162583.18 | |
Likely benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001114098.12 | |
Benign (1) |
no assertion criteria provided
|
- | RCV001353716.9 | |
Benign (1) |
criteria provided, single submitter
|
Apr 1, 2020 | RCV001798059.10 | |
Likely benign (1) |
criteria provided, single submitter
|
Sep 2, 2021 | RCV002504866.8 | |
Benign (1) |
criteria provided, single submitter
|
Apr 19, 2021 | RCV003891462.1 | |
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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
(Jun 18, 2019)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161619.2
First in ClinVar: Feb 17, 2020 Last updated: Jan 07, 2023 |
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 = 0.000345 (less)
|
|
Benign
(Nov 03, 2014)
|
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: SCV000196012.1
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
Tissue: Blood
|
|
Likely benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group D1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001271931.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
|
Likely benign
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Medulloblastoma Malignant tumor of prostate Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002808356.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Benign
(Nov 03, 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: SCV000602816.8
First in ClinVar: Feb 24, 2015 Last updated: Feb 20, 2024 |
|
|
Benign
(Nov 19, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212999.6
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 11, 2015)
|
criteria provided, single submitter
Method: research
|
Hereditary Breast and Ovarian Cancer Syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000212197.1 First in ClinVar: Jan 31, 2016 Last updated: Jan 31, 2016 |
Indication for testing: adults with personal and/or family history of colorectal cancer and/or polyps
|
|
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: SCV001139208.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
Benign
(Apr 01, 2020)
|
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: SCV002043523.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
Benign
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002025846.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 4
Geographic origin: South Africa
|
|
Benign
(Sep 24, 2014)
|
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: SCV000494363.2
First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022 |
|
|
Likely benign
(Jan 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: SCV000154049.2
First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022 |
|
|
Benign
(Jan 02, 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: SCV000683949.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000073456.14
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
Benign
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
BRCA2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805775.2
First in ClinVar: Feb 24, 2015 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
(Jan 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Vantari Genetics
Accession: SCV000267025.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
|
|
Benign
(Apr 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000586980.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
|
|
Likely benign
(Jul 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593731.1
First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
|
|
Likely benign
(Jul 12, 2017)
|
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: SCV000679725.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
|
|
Benign
(Oct 21, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000167408.11
First in ClinVar: Jun 23, 2014 Last updated: Dec 02, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
Benign
(Oct 09, 2014)
|
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: SCV000743345.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
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: SCV000744537.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Benign
(Feb 10, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000202302.7
First in ClinVar: Jan 29, 2015 Last updated: Sep 22, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Likely benign
(Mar 06, 2018)
|
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: SCV000383779.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
|
Benign
(Sep 29, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002531919.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Benign
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010311.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
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: SCV002551790.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
|
|
Likely benign
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493633.27
First in ClinVar: Feb 24, 2015 Last updated: Apr 15, 2024 |
Comment:
BRCA2: BP4, BS2
Number of individuals with the variant: 27
|
|
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: SCV000147293.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 43
Observation 2:
Number of individuals with the variant: 2
Geographic origin: Austria
Observation 3:
Number of individuals with the variant: 2
Geographic origin: Netherlands
Observation 4:
Number of individuals with the variant: 1
Geographic origin: French Canadian
Observation 5:
Number of individuals with the variant: 1
Geographic origin: Native American
Observation 6:
Number of individuals with the variant: 12
Geographic origin: Western European
Observation 7:
Number of individuals with the variant: 1
Geographic origin: Western, Central/Eastern European
Observation 8:
Number of individuals with the variant: 2
Ethnicity/Population group: Ashkenazi
Observation 9:
Number of individuals with the variant: 2
Ethnicity/Population group: Caucasian
Geographic origin: Germany
Observation 10:
Number of individuals with the variant: 4
Ethnicity/Population group: Central/Eastern European
Observation 11:
Number of individuals with the variant: 18
Ethnicity/Population group: Western European
Observation 12:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American
|
|
Likely benign
(Jul 24, 2014)
|
no assertion criteria provided
Method: literature only
|
hereditary breast and ovarian cancer, BROVCA2
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000187731.1
First in ClinVar: Aug 15, 2014 Last updated: Aug 15, 2014 |
|
|
Likely benign
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Breast cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190113.1 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
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733316.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799045.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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: SCV001956346.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
probably not pathogenic
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043229.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Likely benign.
Number of individuals with the variant: 2
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
|
|
Benign
(Mar 08, 2017)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778718.1
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
|
|
Likely benign
(Nov 14, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000787953.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592177.2 First in ClinVar: Oct 22, 2016 Last updated: Apr 13, 2021 |
Comment:
The p.Val2728Ile variant was identified in 26 of 7026 proband chromosomes (frequency: 0.004) from individuals or families with breast, prostate or melanoma cancers, and was … (more)
The p.Val2728Ile variant was identified in 26 of 7026 proband chromosomes (frequency: 0.004) from individuals or families with breast, prostate or melanoma cancers, and was present in 4 of 1852 control chromosomes (frequency: 0.002) from healthy individuals (Sinilnikova 1999, Diez 2003, Haffy 2006, Luedeke 2009, Capanu 2011, Kuusisto 2011, Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rs28897749 “With Other, untested allele”, in NHLBI Exome Sequencing Project (Exome Variant Server) in 39 of 8600 European American and 4 of 4406 African American; in HAPMAP-CEU in 2 of 224 chromosomes (frequency: 0.009) and in HAPMAP-MEX in 3 of 98 chromosomes(frequency: 0.031). In Exome Aggregation Consortium (ExAC) database the variant is found in 216 of 66738 (I homozygote) European (Non-Finnish), 18 of 6614 European (Finnish), 10 of 10404 African, 2 of 11576 Latino and 1 in 908 in Other alleles, increasing the likelihood this could be a low frequency benign variant. The variant was not found in East Asian and South Asian. The variant was identified in LOVD (7x predicted neutral), the ClinVar database (classified as a Benign variant by Invitae (Jun26, 2015), GeneDx (Oct21, 2013), Emory Genetics (Feb10, 2014), Ambry Genetics (Nov19, 2014), Molecular Genetics Diagnostic-CHEO, BIC (May29, 2002) and as Likely Benign by Counsyl (Jan02, 2014), Pathway Genomics (Jul24, 2014), CSER-University of Washington (Jun01, 2014), Biesecker Lab ClinSeq Project (Jul13, 2012); no classification was provided by ITMI. The variant was reported in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “benign” by 2 clinical laboratories), the BIC database (92X with NO clinical importance), and UMD (95X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2:c.1257delT (p.Cys419TrpfsX11), c.7230delT (p.Phe2410LeufsX59), c.6209_6212delAAAG (p.Glu2070ValfsX10), and BRCA1:c.5123C>A (p.Ala1708Glu), c.2308delT (p.Ser770HisfsX22), c.4065_4068delTCAA (p.Asn1355LysfsX10), c.5137delG (p.Val1713X), increasing the likelihood that the p.Val2728Ile variant does not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). The Val2728 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In addition, the variant amino acid Ile (isoleucine) is present in other mammals and lower organisms increasing the likelihood that this variant does not have clinical significance. Overrepresentation of this variant had conferred 2.3-fold increased risk for sporadic prostate cancer and a 6-fold increased risk for familial prostate cancers, however larger sample sizes and replication studies are necessary to clarify the role of the variant in prostate cancer (Luedeke 2009). The c.8182G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as Benign. (less)
Number of individuals with the variant: 6
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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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: SCV001906143.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004243807.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000084514.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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 |
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Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
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 |
Role of rare variants in undetermined multiple adenomatous polyposis and early-onset colorectal cancer. | Lefevre JH | Journal of human genetics | 2012 | PMID: 22875147 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. | Kote-Jarai Z | British journal of cancer | 2011 | PMID: 21952622 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. | Capanu M | Genetic epidemiology | 2011 | PMID: 21520273 |
Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. | Kuusisto KM | Breast cancer research : BCR | 2011 | PMID: 21356067 |
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 |
Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes. | Luedeke M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2009 | PMID: 19861517 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. | Kuznetsov SG | Nature medicine | 2008 | PMID: 18607349 |
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 |
Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. | Simard J | Journal of medical genetics | 2007 | PMID: 16905680 |
Patients with an unclassified genetic variant in the BRCA1 or BRCA2 genes show different clinical features from those with a mutation. | Gómez-García EB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 15800311 |
Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. | Hearle N | Investigative ophthalmology & visual science | 2003 | PMID: 12556369 |
Characterization of common BRCA1 and BRCA2 variants. | Deffenbaugh AM | Genetic testing | 2002 | PMID: 12215251 |
Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. | Murphy KM | Cancer research | 2002 | PMID: 12097290 |
Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations. | Warren M | Human molecular genetics | 2002 | PMID: 11929857 |
Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer. | Steinmann D | British journal of cancer | 2001 | PMID: 11556836 |
Germline brca2 sequence variants in patients with ocular melanoma. | Sinilnikova OM | International journal of cancer | 1999 | PMID: 10399947 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 | - | - | - | - |
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Text-mined citations for rs28897749 ...
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.