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NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(4);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Jan 7, 2021)
Last evaluated:
Apr 8, 2020
Accession:
VCV000055570.7
Variation ID:
55570
Description:
single nucleotide variant
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NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala)

Allele ID
70237
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 43047694 (GRCh38) GRCh38 UCSC
17: 41199711 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000017.10:g.41199711G>C
NC_000017.11:g.43047694G>C
NM_007294.4:c.5416C>G MANE Select NP_009225.1:p.Pro1806Ala missense
... more HGVS
Protein change
P1806A, P1759A, P677R, P1827A, P702A
Other names
-
Canonical SPDI
NC_000017.11:43047693:G:C
Functional consequence
functionally_normal [Sequence Ontology SO:0002219]
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5416C>G, a MISSENSE variant, produced a function score of 0.1, corresponding to a functional classification of FUNCTIONAL. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute,University of Washington]
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Links
dbSNP: rs80357241
ClinGen: CA003580
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter Jan 20, 2020 RCV001174629.1
Likely benign 1 criteria provided, single submitter Mar 13, 2020 RCV001283908.1
Likely benign 1 criteria provided, single submitter Apr 8, 2020 RCV001419359.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Mar 24, 2020 RCV000164214.3
Uncertain significance 2 no assertion criteria provided Nov 14, 1997 RCV000112648.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
BRCA1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
11983 12150

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Jan 20, 2020)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001337835.1
Submitted: (Apr 29, 2020)
Evidence details
Publications
PubMed (7)
Comment:
Variant summary: BRCA1 c.5416C>G (p.Pro1806Ala) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of … (more)
Likely benign
(Mar 14, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000214835.4
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (4)
Comment:
In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Uncertain significance
(Mar 24, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV001352269.1
Submitted: (May 19, 2020)
Comment:
This missense variant replaces proline with alanine at codon 1806 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
Evidence details
Likely benign
(Mar 13, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: unknown
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469396.1
Submitted: (Dec 31, 2020)
Evidence details
Publications
PubMed (7)
Likely benign
(Apr 08, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Invitae
Accession: SCV001621611.1
Submitted: (Jan 07, 2021)
Evidence details
Uncertain significance
(Nov 14, 1997)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145505.1
Submitted: (Mar 28, 2014)
Evidence details
not provided
(-)
no assertion provided
Method: in vitro
Breast-ovarian cancer, familial 1
Allele origin: not applicable
Brotman Baty Institute,University of Washington
Accession: SCV001242741.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)

Functional evidence

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Functional consequence Method Result Submitter Supporting information
functionally_normal
  1. saturation genome editing in haploid cells
  2. Method citation(s):
  1. FUNCTIONAL:0.0981067115118336
Brotman Baty Institute,University of Washington
Accession: SCV001242741.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5416C>G, a MISSENSE variant, produced a function score of 0.1, corresponding to a functional classification of FUNCTIONAL. … (more)

Citations for this variant

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Title Author Journal Year Link
Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. Fernandes VC The Journal of biological chemistry 2019 PMID: 30765603
Accurate classification of BRCA1 variants with saturation genome editing. Findlay GM Nature 2018 PMID: 30209399
Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Lee MS Cancer research 2010 PMID: 20516115
Toward classification of BRCA1 missense variants using a biophysical approach. Rowling PJ The Journal of biological chemistry 2010 PMID: 20378548
Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Carvalho MA Cancer research 2007 PMID: 17308087
Functional impact of missense variants in BRCA1 predicted by supervised learning. Karchin R PLoS computational biology 2007 PMID: 17305420
Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Mirkovic N Cancer research 2004 PMID: 15172985
Functional characterization of BRCA1 sequence variants using a yeast small colony phenotype assay. Coyne RS Cancer biology & therapy 2004 PMID: 15004537
Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation. Hayes F Cancer research 2000 PMID: 10811118
BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. Shattuck-Eidens D JAMA 1997 PMID: 9333265
https://sge.gs.washington.edu/BRCA1/ - - - -

Text-mined citations for rs80357241...

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These 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 Jun 14, 2021