ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7847C>T (p.Ser2616Phe)
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(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7847C>T (p.Ser2616Phe)
Variation ID: 630829 Accession: VCV000630829.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32362564 (GRCh38) [ NCBI UCSC ] 13: 32936701 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 20, 2019 Jul 7, 2024 Mar 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7847C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Ser2616Phe missense NC_000013.11:g.32362564C>T NC_000013.10:g.32936701C>T NG_012772.3:g.52085C>T LRG_293:g.52085C>T LRG_293t1:c.7847C>T LRG_293p1:p.Ser2616Phe - Protein change
- S2616F
- Other names
- p.Ser2616Phe
- Canonical SPDI
- NC_000013.11:32362563:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_abnormal Sequence Ontology [SO:0002218]
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18955 | 19114 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2021 | RCV000776833.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 13, 2024 | RCV001362915.11 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Uncertain significance
(Jan 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000912491.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces serine with phenylalanine at codon 2616 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces serine with phenylalanine at codon 2616 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 19016756) and co-occurred with BRCA2 c.475+1G>A in one case of Fanconi Anemia in the literature (PMID: 30792206). 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)
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Uncertain significance
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001558968.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2616 of the BRCA2 protein (p.Ser2616Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2616 of the BRCA2 protein (p.Ser2616Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, clinical features of Fanconi anemia, and/or ovarian cancer (PMID: 19016756, 30287823, 30792206, 37067535). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 630829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32444794, 37731132). 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)
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Uncertain significance
(Dec 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002670051.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S2616F variant (also known as c.7847C>T), located in coding exon 16 of the BRCA2 gene, results from a C to T substitution at nucleotide … (more)
The p.S2616F variant (also known as c.7847C>T), located in coding exon 16 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7847. The serine at codon 2616 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was observed with an allele frequency of 0.00043 in 7,051 unselected female breast cancer patients and was not observed in 11,241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.00024 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in 2/135 Japanese patients with suspected HBOC (Sugano K et al. Cancer Sci, 2008 Oct;99:1967-76). This amino acid position is 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)
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Likely pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: yes, not applicable
Allele origin:
germline,
not applicable
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Dept of Medical Genetics, NHO Tokyo Medical Center
Accession: SCV004046643.2
First in ClinVar: Oct 28, 2023 Last updated: Nov 04, 2023 |
Comment:
The p.Ser2616Phe variant in BRCA2 has been reported in 10 Japanese patients from 7 families with breast and ovarian cancers (Yamazawa 2023). This variant was … (more)
The p.Ser2616Phe variant in BRCA2 has been reported in 10 Japanese patients from 7 families with breast and ovarian cancers (Yamazawa 2023). This variant was absent from global large population studies, but 11 Japanese variant carriers were registered in the Japanase population database ToMMo 54KJPN. A Japanese patient with Fanconi anemia with compound heterozygous variants p.Ser2616Phe and c.475+1G>A in BRCA2 was reported, where c.475+1G>A was known to be pathogenic (Mori 2019). Multiple lines of computational evidence support a deleterious effect of the p.Ser2616Phe. Additionally, in vitro functional assay named MANO-B method demonstrated that the p.Ser2616Phe had a pathogenic effect (Ikegami 2020, Yamazawa 2023). In summary, the p.Ser2616Phe variant meets the ACMG/AMP criteria to be classified as likely pathogenic. In addition, according to the recent report by Guo et al., a conventional homologous recombination assay coupled with a complementary statistical logistic regression prediction model that integrated six in silico functional prediction tools also demonstrated that the BRCA2 p.Ser2616Phe variant is pathogenic (Guo 2023). (less)
Observation 1:
Number of individuals with the variant: 10
Clinical Features:
Breast carcinoma (present) , Ovarian carcinoma (present)
Age: 23-72 years
Sex: female
Ethnicity/Population group: Japanese
Geographic origin: Japan
Method: Myriad BRACAnalysis is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR.
Testing laboratory: Myriad Genetic Laboratories
Testing laboratory interpretation: Uncertain significance
Observation 2:
Method: A total of 244 BRCA2 variants was constructed by site-directed mutagenesis and subcloned into the piggyBac vector containing a unique DNA barcode sequence. DLD1 BRCA2 (-/-) cells, derived from a BRCA2 knockout human colorectal adenocarcinoma cell line, were individually co-transfected with the BRCA2 variant constructs and transposase expression vector. After the selection of stable transfectants using puromycin, equal amounts of DLD1 cells were mixed and cultured with PARP inhibitor (niraparib) or dimethyl sulfoxide. The barcode sequences were PCR amplified with genomic DNA extracted from the cell mixture and then subjected to deep sequence analysis to calculate their relative abundances. Based on the VarCall model, relative viability data were analyzed using a Hamiltonian Monte Carlo algorithm for Bayesian inference. The Bayes factor (BF), defined as the strength of evidence in favor of pathogenicity, was calculated for each variant with a noninformative prior probability.
Result:
The Bayes factor (BF) of this variant was estimated to be 6.09 × 10^2. A five-tier functional classification based on the BF was assigned according to established criteria consistent with the ACMG/AMP guidelines as follows: fClass 1 (benign; BF ≤ 0.003), fClass 2 (likely benign; 0.003 < BF ≤ 0.053), fClass 3 (intermediate; 0.053 < BF < 18.7), fClass 4 (likely pathogenic; 18.7 ≤ BF < 350), or fClass 5 (pathogenic; 350 ≤ BF). Thus, the variant was categorized as fClass 5 (pathogenic).
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Likely pathogenic
(Mar 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039360.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: BRCA2 c.7847C>T (p.Ser2616Phe) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of … (more)
Variant summary: BRCA2 c.7847C>T (p.Ser2616Phe) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251232 control chromosomes. c.7847C>T has been reported in the literature in multiple Japanese individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Yamazawa_2023) and at an in trans state along with a pathoenic splicing variant in at-least one patient with Fanconi anemia (Mori_2019, Radulovic_2023). Large case-control studies of Biliary tract cancer and Breast cancer however reported insignificant results of this variant (Okawa_2023, Momozawa_2018). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function. Such studies consistently categoried the variant Pathogenic via conventional homologous recombination (HR) assays (Guo_2023) and PARP inhibitor sensitivity-based MANO-B method (Yamazawa_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37731132, 30287823, 30792206, 36243179, 36721989, 37067535). ClinVar contains an entry for this variant (Variation ID: 630829). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_abnormal
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Method citation(s):
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Dept of Medical Genetics, NHO Tokyo Medical Center
Accession: SCV004046643.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Functional evaluation of BRCA1/2 variants of unknown significance with homologous recombination assay and integrative in silico prediction model. | Guo Q | Journal of human genetics | 2023 | PMID: 37731132 |
The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition. | Yamazawa K | Cancer science | 2023 | PMID: 37067535 |
A novel cancer risk prediction score for the natural course of FA patients with biallelic BRCA2/FANCD1 mutations. | Radulovic I | Human molecular genetics | 2023 | PMID: 36721989 |
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
High-throughput functional evaluation of BRCA2 variants of unknown significance. | Ikegami M | Nature communications | 2020 | PMID: 32444794 |
Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. | Mori M | Haematologica | 2019 | PMID: 30792206 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer. | Sugano K | Cancer science | 2008 | PMID: 19016756 |
Text-mined citations for rs1174303167 ...
HelpRecord last updated Sep 29, 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.