ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8452G>T (p.Val2818Phe)
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.
Likely pathogenic(1); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.8452G>T (p.Val2818Phe)
Variation ID: 481607 Accession: VCV000481607.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32370522 (GRCh38) [ NCBI UCSC ] 13: 32944659 (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 Jan 1, 2018 May 1, 2024 Jan 12, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.8452G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Val2818Phe missense NC_000013.11:g.32370522G>T NC_000013.10:g.32944659G>T NG_012772.3:g.60043G>T LRG_293:g.60043G>T LRG_293t1:c.8452G>T LRG_293p1:p.Val2818Phe - Protein change
- V2818F
- Other names
- -
- Canonical SPDI
- NC_000013.11:32370521:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 |
18726 | 18884 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 11, 2019 | RCV000566230.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Sep 2, 2021 | RCV001320393.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV001821668.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
May 8, 2023 | RCV003227793.1 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV003234782.4 |
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
(Jun 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070244.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.8452G>T, in exon 19 that results in an amino acid change, p.Val2818Phe. This sequence … (more)
DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.8452G>T, in exon 19 that results in an amino acid change, p.Val2818Phe. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Val2818Phe change has been reported in one Saudi Arabian individual with breast cancer (PMID: 30199306). The p.Val2818Phe change affects a highly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val2818Phe substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val2818Phe change remains unknown at this time. (less)
|
|
Uncertain significance
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001511175.3
First in ClinVar: Mar 14, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine with phenylalanine at codon 2818 of the BRCA2 protein (p.Val2818Phe). The valine residue is highly conserved and there is a … (more)
This sequence change replaces valine with phenylalanine at codon 2818 of the BRCA2 protein (p.Val2818Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30199306). ClinVar contains an entry for this variant (Variation ID: 481607). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: research
|
Fanconi anemia complementation group D1
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924290.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
|
|
Uncertain significance
(Jun 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003932765.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
A variant of uncertain significance was detected in this sample. This sequence change replaces valine at codon 2818 is by phenylalanine, an amino acid with … (more)
A variant of uncertain significance was detected in this sample. This sequence change replaces valine at codon 2818 is by phenylalanine, an amino acid with highly similar properties., which located in coding exon 19 of the BRCA2 gene (NM_000059.3), results from a G to T substitution at nucleotide position 8452. This amino acid position is not highly conserved. This variant is not present in population databases (gnomAD ) nor in our local databases . This variant reported in ClinVar database (ID: 481607) .Also it was previously reported in one Saudi Arabian individual with breast cancer (PMID: 30199306). This alteration is predicted to be possibly damaging and deleterious by (PolyPhen , EIGEN PC, FATHMM , LRT,Mutation taster , DANN, M-CAP, MVP , Align GVGD, REVEL and SIFT). In summary, Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val2818Phe change remains unknown at this time. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Sex: female
|
|
Uncertain significance
(Jan 12, 2024)
|
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: SCV004804499.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: BRCA2 c.8452G>T (p.Val2818Phe) results in a non-conservative amino acid change located in the OB2 domain (IPR048262) of the encoded protein sequence. Four of … (more)
Variant summary: BRCA2 c.8452G>T (p.Val2818Phe) results in a non-conservative amino acid change located in the OB2 domain (IPR048262) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8452G>T has been reported in the literature in individuals from Saudi Arabia, including at least one individual affected with breast cancer (e.g., Abulkhair_2018), as well as a homozygous individual for whom clinical details were not provided, although the individual was reported to have a sibling with leukemia and suspected Fanconi anemia (e.g., AlAbdi_2021, Monies_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30199306, 34316023, 37344829). ClinVar contains an entry for this variant (Variation ID: 481607). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain Significance
(Aug 15, 2023)
|
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: SCV004826380.1
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)
|
Comment:
This missense variant replaces valine with phenylalanine at codon 2818 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with phenylalanine at codon 2818 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30199306). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Mar 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000666160.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.V2818F variant (also known as c.8452G>T), located in coding exon 18 of the BRCA2 gene, results from a G to T substitution at nucleotide … (more)
The p.V2818F variant (also known as c.8452G>T), located in coding exon 18 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8452. The valine at codon 2818 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(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: SCV004243820.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
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 |
---|---|---|---|---|
The clinical utility of rapid exome sequencing in a consanguineous population. | Monies D | Genome medicine | 2023 | PMID: 37344829 |
Residual risk for additional recessive diseases in consanguineous couples. | AlAbdi L | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34316023 |
Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer. | Abulkhair O | Journal of global oncology | 2018 | PMID: 30199306 |
Text-mined citations for rs80359094 ...
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.