ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5510_5511delinsCT (p.Trp1837Ser)
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_007294.4(BRCA1):c.5510_5511delinsCT (p.Trp1837Ser)
Variation ID: 1065962 Accession: VCV001065962.7
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 17q21.31 17: 43045759-43045760 (GRCh38) [ NCBI UCSC ] 17: 41197776-41197777 (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 10, 2021 Feb 28, 2024 Oct 4, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- W1790S, W1837S, W1858S, W733S, W1683S, W1770S, W1793S, W1794S, W1796S, W1811S, W1834S, W1857S, W1859S, W425S, W557S, W620S, W652S, W666S, W667S, W687S, W689S, W692S, W695S, W969S, W1540S, W1668S, W1710S, W1747S, W1748S, W1766S, W1767S, W1809S, W1835S, W621S, W625S, W663S, W685S, W691S, W694S, W732S, W1708S, W1724S, W1725S, W1726S, W1749S, W1753S, W1769S, W1788S, W1789S, W1795S, W1810S, W1818S, W1832S, W1833S, W1836S, W566S, W606S, W624S, W644S, W645S, W662S, W664S, W686S, W708S, W709S, W730S, W755S, W1541S, W1709S, W1765S, W1768S, W1817S, W607S, W646S, W654S, W693S, W707S, W731S, W734S, W756S, W968S
- Other names
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- Canonical SPDI
- NC_000017.11:43045758:CC:AG
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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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- 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 | ||
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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
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. |
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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12795 | 14565 |
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. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 27, 2020 | RCV001376823.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2023 | RCV003738058.1 |
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
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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
(Oct 04, 2023)
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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: SCV004564529.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The BRCA1 c.5510_5511delinsCT; p.Trp1837Ser variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1065962). This variant … (more)
The BRCA1 c.5510_5511delinsCT; p.Trp1837Ser variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1065962). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant resulting in the same amino acid change (c.5510G>C; p.Trp1837Ser) has been reported in individuals with breast and/or ovarian cancer (Kechin 2023, Wang 2019), and computational analyses predict that the p.Trp1837Ser variant is deleterious (REVEL: 0.854). Additionally, other amino acid substitutions at this codon (Arg, Gly, Cys) have been reported in individuals with breast and/or ovarian cancer (Abkevich 2004, Tran 2022, Wan 2019). Based on available information, the c.5510_5511delinsCT; p.Trp1837Ser variant is considered to be likely pathogenic. References: Abkevich V et al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004 Jul;41(7):492-507. PMID: 15235020. Kechin A et al. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023 Jan;197(2):387-395. PMID: 36367610. Tran VT et al. Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort. Front Oncol. 2022 Jan 5;11:789659. PMID: 35070997. Wan Q et al. Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer. Fam Cancer. 2021 Apr;20(2):85-95. PMID: 32803532. Wang J et al. Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes. Cancer Med. 2019 May;8(5):2074-2084. PMID: 30982232. (less)
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Likely pathogenic
(Feb 27, 2020)
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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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Invitae
Accession: SCV001573996.3
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tryptophan with serine at codon 1837 of the BRCA1 protein (p.Trp1837Ser). The tryptophan residue is highly conserved and there is a … (more)
This sequence change replaces tryptophan with serine at codon 1837 of the BRCA1 protein (p.Trp1837Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. 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. This variant disrupts the p.Trp1837 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28324225, 11802209, 27741520, 8968102, 15689452, 20516115, 27802165, 16267036). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt BRCA1 protein function. Additionally, another variant causing the same amino acid change, c.5510G>C, has been reported to affect BRCA1 protein function (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. (less)
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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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Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. | Meisel C | Archives of gynecology and obstetrics | 2017 | PMID: 28324225 |
Yeast cells reveal the misfolding and the cellular mislocalization of the human BRCA1 protein. | Thouvenot P | Journal of cell science | 2016 | PMID: 27802165 |
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. | Fernandes GC | Oncotarget | 2016 | PMID: 27741520 |
Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
Classification of BRCA1 missense variants of unknown clinical significance. | Phelan CM | Journal of medical genetics | 2005 | PMID: 15689452 |
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. | Meindl A | International journal of cancer | 2002 | PMID: 11802209 |
Identification of seven new BRCA1 germline mutations in Italian breast and breast/ovarian cancer families. | Montagna M | Cancer research | 1996 | PMID: 8968102 |
Text-mined citations for rs2152547868 ...
HelpRecord last updated Mar 05, 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.