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NM_007294.4(BRCA1):c.5074G>A (p.Asp1692Asn)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
10 (Most recent: Sep 9, 2021)
Last evaluated:
Sep 5, 2020
Accession:
VCV000037632.9
Variation ID:
37632
Description:
single nucleotide variant
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NM_007294.4(BRCA1):c.5074G>A (p.Asp1692Asn)

Allele ID
46188
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 43067608 (GRCh38) GRCh38 UCSC
17: 41219625 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_292:g.150376G>A
LRG_292t1:c.5074G>A LRG_292p1:p.Asp1692Asn
U14680.1:n.5193G>A
... more HGVS
Protein change
D1692N, D1645N, D1713N, D588N
Other names
5193G>A
Canonical SPDI
NC_000017.11:43067607:C:T
Functional consequence
functionally_abnormal [Sequence Ontology SO:0002218]
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5074G>A, a MISSENSE variant, produced a function score of -1.86, corresponding to a functional classification of LOSS_OF_FUNCTION. 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
-
Links
dbSNP: rs80187739
ClinGen: CA003201
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 11, 2020 RCV000217586.3
Pathogenic 4 criteria provided, single submitter Oct 2, 2015 RCV000031213.8
Likely pathogenic 1 criteria provided, single submitter Jul 3, 2018 RCV000255870.2
Pathogenic 2 criteria provided, single submitter Sep 5, 2020 RCV000496924.2
Pathogenic 1 criteria provided, single submitter Dec 1, 2013 RCV001659879.1
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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
12270 12437

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Mar 11, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000904696.2
Submitted: (May 19, 2020)
Comment:
This missense variant replaces aspartic acid with asparagine at codon 1692 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant … (more)
Evidence details
Likely pathogenic
(Nov 21, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000273244.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
The c.5074G>A variant (also known as p.D1692N), located in coding exon 15 of the BRCA1 gene, results from a G to A substitution at nucleotide … (more)
Pathogenic
(Oct 02, 2015)
criteria provided, single submitter
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326135.3
Submitted: (Oct 28, 2016)
Evidence details
Likely pathogenic
(Jul 03, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000322096.7
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This variant is denoted BRCA1 c.5074G>A at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 5193G>A. Although the nucleotide … (more)
Pathogenic
(Sep 05, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Invitae
Accession: SCV001585898.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (13)
Comment:
This sequence change replaces aspartic acid with asparagine at codon 1692 of the BRCA1 protein (p.Asp1692Asn). The aspartic acid residue is highly conserved and there … (more)
Pathogenic
(Dec 01, 2013)
criteria provided, single submitter
Method: curation
Breast-ovarian cancer, familial 1
Breast-ovarian cancer, familial 2
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Research and Development, ARUP Laboratories
Accession: SCV001877434.1
Submitted: (Sep 09, 2021)
Evidence details
Publications
PubMed (2)
Other databases
https://arup.utah.edu/database/B…
Pathogenic
(May 29, 2002)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145293.1
Submitted: (Mar 28, 2014)
Evidence details
Likely pathogenic
(Jul 25, 2006)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053813.5
Submitted: (Jul 02, 2012)
Evidence details
Likely pathogenic
(Dec 17, 2015)
no assertion criteria provided
Method: research
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587454.1
Submitted: (Aug 04, 2017)
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: SCV001244020.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)

Functional evidence

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Functional consequence Method Result Submitter Supporting information
functionally_abnormal
  1. saturation genome editing in haploid cells
  2. Method citation(s):
  1. LOSS_OF_FUNCTION:-1.86484269773559
Brotman Baty Institute,University of Washington
Accession: SCV001244020.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5074G>A, a MISSENSE variant, produced a function score of -1.86, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)

Citations for this variant

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Title Author Journal Year Link
Accurate classification of BRCA1 variants with saturation genome editing. Findlay GM Nature 2018 PMID: 30209399
Protein stability versus function: effects of destabilizing missense mutations on BRCA1 DNA repair activity. Gaboriau DC The Biochemical journal 2015 PMID: 25748678
Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. Ahlborn LB Breast cancer research and treatment 2015 PMID: 25724305
Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. Wappenschmidt B PloS one 2012 PMID: 23239986
Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO). Lecarpentier J Breast cancer research : BCR 2012 PMID: 22762150
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
Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Thomassen M Breast cancer research and treatment 2012 PMID: 21769658
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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Buratti E Nucleic acids research 2007 PMID: 17576681
BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Rafnar T European journal of cancer (Oxford, England : 1990) 2004 PMID: 15571962
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. Abkevich V Journal of medical genetics 2004 PMID: 15235020
Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Vallon-Christersson J Human molecular genetics 2001 PMID: 11157798
Germline BRCA1 alterations in a population-based series of ovarian cancer cases. Janezic SA Human molecular genetics 1999 PMID: 10196379
Statistical features of human exons and their flanking regions. Zhang MQ Human molecular genetics 1998 PMID: 9536098
Identification of a novel splice-site mutation of the BRCA1 gene in two breast cancer families: screening reveals low frequency in Icelandic breast cancer patients. Bergthorsson JT Human mutation 1998 PMID: 9452084
Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer. Arason A American journal of human genetics 1993 PMID: 8460636
https://arup.utah.edu/database/BRCA/Variants/BRCA1.php - - - -
https://sge.gs.washington.edu/BRCA1/ - - - -

Text-mined citations for rs80187739...

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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 Sep 18, 2021