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NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro)

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Interpretation:
Pathogenic​

Review status:
reviewed by expert panel
Submissions:
10 (Most recent: Sep 9, 2021)
Last evaluated:
Aug 10, 2015
Accession:
VCV000055510.9
Variation ID:
55510
Description:
single nucleotide variant
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NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro)

Allele ID
70177
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 43051104 (GRCh38) GRCh38 UCSC
17: 41203121 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P38398:p.Leu1764Pro
LRG_292:g.166880T>C
LRG_292t1:c.5291T>C LRG_292p1:p.Leu1764Pro
... more HGVS
Protein change
L1764P, L1717P, L660P, L1785P
Other names
5410T>C
Canonical SPDI
NC_000017.11:43051103:A:G
Functional consequence
functionally_abnormal [Sequence Ontology SO:0002218]
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5291T>C, a MISSENSE variant, produced a function score of -1.99, 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
BRCA1-HCI: BRCA1_00049
ClinGen: CA003449
UniProtKB: P38398#VAR_063908
dbSNP: rs80357281
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 5 reviewed by expert panel Aug 10, 2015 RCV000112604.3
Pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 3, 2020 RCV000588744.2
Likely pathogenic 1 criteria provided, single submitter Jan 30, 2020 RCV000509995.3
Pathogenic 1 criteria provided, single submitter Jan 20, 2020 RCV001664074.1
Pathogenic 1 no assertion criteria provided - RCV001528204.2
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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
12270 12437

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 10, 2015)
reviewed by expert panel
Method: curation
Breast-ovarian cancer, familial 1
Allele origin: germline
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000244395.1
Submitted: (Aug 17, 2015)
Evidence details
Publications
PubMed (1)
Other databases
http://hci-exlovd.hci.utah.edu/v…
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on … (more)
Pathogenic
(Jan 20, 2020)
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: SCV001878757.1
Submitted: (Sep 09, 2021)
Evidence details
Publications
PubMed (2)
Other databases
https://arup.utah.edu/database/B…
Likely pathogenic
(Jan 30, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000607979.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (7)
Comment:
The p.L1764P variant (also known as c.5291T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide … (more)
Pathogenic
(Mar 03, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Invitae
Accession: SCV001578892.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (13)
Comment:
This sequence change replaces leucine with proline at codon 1764 of the BRCA1 protein (p.Leu1764Pro). The leucine residue is moderately conserved and there is a … (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: SCV000326250.3
Submitted: (Oct 28, 2016)
Evidence details
Pathogenic
(Jan 31, 2017)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699234.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (9)
Comment:
Variant summary: The BRCA1 c.5291T>C (p.Leu1764Pro) variant located in the BRCT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico … (more)
Pathogenic
(Feb 14, 2018)
criteria provided, single submitter
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: unknown
Counsyl
Accession: SCV000786057.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (11)
Uncertain significance
(Feb 20, 2004)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145441.1
Submitted: (Mar 28, 2014)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739520.3
Submitted: (Sep 02, 2021)
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: SCV001243050.1
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:-1.98674456258502
Brotman Baty Institute,University of Washington
Accession: SCV001243050.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5291T>C, a MISSENSE variant, produced a function score of -1.99, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)

Citations for this variant

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Title Author Journal Year Link
Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of <i>BRCA1</i> BRCT Variants on Cancer Risk. Petitalot A Molecular cancer research : MCR 2019 PMID: 30257991
Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria. Hoyer J BMC cancer 2018 PMID: 30257646
Accurate classification of BRCA1 variants with saturation genome editing. Findlay GM Nature 2018 PMID: 30209399
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Rebbeck TR Human mutation 2018 PMID: 29446198
Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making. Thouvenot P PLoS genetics 2016 PMID: 27272900
HBOC multi-gene panel testing: comparison of two sequencing centers. Schroeder C Breast cancer research and treatment 2015 PMID: 26022348
A high-throughput functional complementation assay for classification of BRCA1 missense variants. Bouwman P Cancer discovery 2013 PMID: 23867111
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
A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. Iversen ES Jr Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2011 PMID: 21447777
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
Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Tavtigian SV Human mutation 2008 PMID: 18951461
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. Spearman AD Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 PMID: 18824701
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Easton DF American journal of human genetics 2007 PMID: 17924331
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
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
Missense mutations in the BRCT domain of BRCA-1 from high-risk women frequently perturb strongly hydrophobic amino acids conserved among mammals. Figge MA Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2004 PMID: 15184261
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA1&action=search_all&search_Variant%2FDNA=c.5291T%3EC - - - -
https://arup.utah.edu/database/BRCA/Variants/BRCA1.php - - - -
https://sge.gs.washington.edu/BRCA1/ - - - -

Text-mined citations for rs80357281...

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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 23, 2021