Variant summary: BRCA2 c.8647C>T (p.Pro2883Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8647C>T has been reported in the literature in at-least one individual affected with unilateral breast cancer ((example, Borg_2010, Capanu_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.2722G>T, p.Glu908Ter; BRCA1 exon13ins6kb), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no effect on splicing, however, this does not allow convincing conclusions about the variant functional effect (example, Acedo_2015). Another likelihood ratio based analysis has predicted the variant to have a neutral impact (example, Karchin_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four reported a classification as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8647C>T (p.Pro2883Ser)
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(2); Likely benign(5)
Uncertain significance(2); Likely benign(5)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.8647C>T (p.Pro2883Ser)
Variation ID: 38175 Accession: VCV000038175.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32376684 (GRCh38) [ NCBI UCSC ] 13: 32950821 (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 1, 2014 Aug 11, 2024 May 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000059.4:c.8647C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Pro2883Ser missense NC_000013.11:g.32376684C>T NC_000013.10:g.32950821C>T NG_012772.3:g.66205C>T LRG_293:g.66205C>T LRG_293t1:c.8647C>T LRG_293p1:p.Pro2883Ser U43746.1:n.8875C>T - Protein change
- P2883S
- Other names
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8875C>T
- Canonical SPDI
- NC_000013.11:32376683:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18967 | 19126 | |
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. |
|---|---|---|---|---|
| Likely benign (3) |
criteria provided, single submitter
|
May 28, 2019 | RCV000031758.13 | |
| Likely benign (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV000045590.19 | |
| Likely benign (1) |
criteria provided, single submitter
|
Nov 16, 2020 | RCV000417546.10 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 15, 2024 | RCV000567301.18 | |
| Likely benign (3) |
criteria provided, single submitter
|
Feb 19, 2021 | RCV001703441.11 |
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
(Sep 24, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002531963.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.8647C>T (p.P2883S) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 20104584). It was observed in 2/113642 … (more)
The BRCA2 c.8647C>T (p.P2883S) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 20104584). It was observed in 2/113642 chromosomes in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 38175). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
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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: SCV001139223.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(May 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689143.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
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Likely benign
(Nov 16, 2020)
|
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: SCV000695168.2
First in ClinVar: Mar 17, 2018 Last updated: Dec 07, 2020 |
Comment:
Variant summary: BRCA2 c.8647C>T (p.Pro2883Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.8647C>T (p.Pro2883Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8647C>T has been reported in the literature in at-least one individual affected with unilateral breast cancer ((example, Borg_2010, Capanu_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.2722G>T, p.Glu908Ter; BRCA1 exon13ins6kb), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no effect on splicing, however, this does not allow convincing conclusions about the variant functional effect (example, Acedo_2015). Another likelihood ratio based analysis has predicted the variant to have a neutral impact (example, Karchin_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four reported a classification as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign. (less)
|
|
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Likely benign
(Feb 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000512393.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 25382762, 20104584, 19043619, 21520273, 10923033)
|
|
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Likely benign
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000073603.10
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
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Uncertain significance
(May 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000668605.6
First in ClinVar: Jan 01, 2018 Last updated: Aug 11, 2024 |
Comment:
The p.P2883S variant (also known as c.8647C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide … (more)
The p.P2883S variant (also known as c.8647C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8647. The proline at codon 2883 is replaced by serine, an amino acid with similar properties. This variant was detected and reported as an unclassified variant in a unilateral breast cancer patient in a cohort of 705 contralateral and 1398 unilateral breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
|
|
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Likely benign
(Aug 19, 2013)
|
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: SCV000054366.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
|
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Uncertain significance
(Feb 20, 2004)
|
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: SCV000147428.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001951748.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970282.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Comment:
Comment:
This variant is associated with the following publications: (PMID: 25382762, 20104584, 19043619, 21520273, 10923033)
Comment:
The p.P2883S variant (also known as c.8647C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8647. The proline at codon 2883 is replaced by serine, an amino acid with similar properties. This variant was detected and reported as an unclassified variant in a unilateral breast cancer patient in a cohort of 705 contralateral and 1398 unilateral breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
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: BRCA2 c.8647C>T (p.Pro2883Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8647C>T has been reported in the literature in at-least one individual affected with unilateral breast cancer ((example, Borg_2010, Capanu_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.2722G>T, p.Glu908Ter; BRCA1 exon13ins6kb), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no effect on splicing, however, this does not allow convincing conclusions about the variant functional effect (example, Acedo_2015). Another likelihood ratio based analysis has predicted the variant to have a neutral impact (example, Karchin_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four reported a classification as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 25382762, 20104584, 19043619, 21520273, 10923033)
Comment:
The p.P2883S variant (also known as c.8647C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8647. The proline at codon 2883 is replaced by serine, an amino acid with similar properties. This variant was detected and reported as an unclassified variant in a unilateral breast cancer patient in a cohort of 705 contralateral and 1398 unilateral breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. | Acedo A | Human mutation | 2015 | PMID: 25382762 |
| Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. | Capanu M | Genetic epidemiology | 2011 | PMID: 21520273 |
| 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 |
| Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs80359122 ...
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 Nov 03, 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.