ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8057T>C (p.Leu2686Pro)
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
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NM_000059.4(BRCA2):c.8057T>C (p.Leu2686Pro)
Variation ID: 52489 Accession: VCV000052489.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32363259 (GRCh38) [ NCBI UCSC ] 13: 32937396 (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 Apr 1, 2014 May 1, 2024 Oct 5, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8057T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Leu2686Pro missense NC_000013.11:g.32363259T>C NC_000013.10:g.32937396T>C NG_012772.3:g.52780T>C LRG_293:g.52780T>C LRG_293t1:c.8057T>C LRG_293p1:p.Leu2686Pro U43746.1:n.8285T>C - Protein change
- L2686P
- Other names
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- Canonical SPDI
- NC_000013.11:32363258:T:C
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 (1) |
no assertion criteria provided
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Feb 20, 2004 | RCV000113861.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2017 | RCV000479056.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2020 | RCV000568548.8 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 5, 2020 | RCV001264563.10 |
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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Likely pathogenic
(Dec 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883517.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
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Likely pathogenic
(May 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565756.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8285T>C. This variant was observed in an individual diagnosed with Fanconi Anemia who also harbored a pathogenic variant in trans with BRCA2 Leu2686Pro (Dodgshun 2016). This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA2 Leu2686Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2686Pro occurs at a position that is conserved across species and is located in the DNA binding domain, the nuclear export signal motif, and the SHFM1 binding domain (Marston 1999, Yang 2002, Jayesekharan 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2686Pro to be a likely pathogenic variant. (less)
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Likely pathogenic
(Oct 08, 2019)
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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: SCV001340336.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces leucine with proline at codon 2686 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces leucine with proline at codon 2686 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant is deficient in the complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 29988080). This variant has been reported with a pathogenic BRCA2 co-variant in an individual affected with Fanconi anemia with a family history of cancer (PMID: 26740091). This variant was also included in multifactorial analysis studies with discordant reports of pathogenicity (PMID: 21990134, 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 24, 2018)
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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: SCV001574246.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine with proline at codon 2686 of the BRCA2 protein (p.Leu2686Pro). The leucine residue is highly conserved and there is a … (more)
This sequence change replaces leucine with proline at codon 2686 of the BRCA2 protein (p.Leu2686Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). However, this prediction has not been confirmed by published functional studies. In addition, based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Fanconi anemia (PMID: 26740091).  This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52489). (less)
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Likely pathogenic
(Oct 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442781.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment:
Variant summary: BRCA2 c.8057T>C (p.Leu2686Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five … (more)
Variant summary: BRCA2 c.8057T>C (p.Leu2686Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) 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 251264 control chromosomes. c.8057T>C has been reported in the literature in one individual affected with Fanconi Anemia and a biallelic BRCA2 genotype (BRCA2 c.9672dupA (paternal) and c.8057T>C (maternal) (Dodgshun_2016). It was also identified in a proband from a family with Hereditary Breast And Ovarian Cancer (Azzollini_2016). At-least two multifactorial probability based assessments have classified this variant with a high probability of pathogenicity (example, Karchin_2008, Lindor_2012). Several publications report consistent experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Hart_2019). The most pronounced variant effect results in defective homology directed repair. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 10, 2018)
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criteria provided, single submitter
Method: curation
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Hereditary Breast and Ovarian Cancer
Affected status: unknown
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV001478294.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
Comment:
Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), … (more)
Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.2) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.994 and an overall classification of pathogenic. (PS3_strong). There are two likely pathogenic classifications on ClinVar for this variant from accredited USA diagnostic laboratories (Ambry Genetics and GeneDx, 2016) (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (1), UMD (5), BIC (1), and BRCA2 LOVD (1). (less)
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Pathogenic
(Jan 22, 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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Ambry Genetics
Accession: SCV000666009.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.L2686P pathogenic mutation (also known as c.8057T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at … (more)
The p.L2686P pathogenic mutation (also known as c.8057T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8057. The leucine at codon 2686 is replaced by proline, an amino acid with similar properties. This variant was detected in trans with a pathogenic BRCA2 mutation in a patient diagnosed with Fanconi Anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ. Cancer Genet. 2016;209:53-6). This alteration was defective in homology-directed DNA repair (HDR) assays, as well as a mouse ES cell growth assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med. 2019 02;21:293-302; Hart SN et al. Genet. Med. 2019 01;21:71-80). In addition, in a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(Feb 20, 2004)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147259.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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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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The functional impact of variants of uncertain significance in BRCA2. | Mesman RLS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29988080 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. | Guidugli L | American journal of human genetics | 2018 | PMID: 29394989 |
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. | Azzollini J | European journal of internal medicine | 2016 | PMID: 27062684 |
Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. | Dodgshun AJ | Cancer genetics | 2016 | PMID: 26740091 |
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 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
Computational and structural investigation of deleterious functional SNPs in breast cancer BRCA2 gene. | Rajasekaran R | Sheng wu gong cheng xue bao = Chinese journal of biotechnology | 2008 | PMID: 18724707 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs28897746 ...
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.