NM_007294.3(BRCA1):c.4327C>T (p.Arg1443Ter) AND Hereditary breast and ovarian cancer syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Dec 27, 2017
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000048523.11

Allele description

NM_007294.3(BRCA1):c.4327C>T (p.Arg1443Ter)

Gene:

BRCA1:BRCA1, DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_007294.3(BRCA1):c.4327C>T (p.Arg1443Ter)

Other names:

p.R1443X:CGA>TGA

HGVS:

NC_000017.11:g.43082434G>A
NG_005905.2:g.135550C>T
NM_007294.3:c.4327C>T
NM_007299.3:c.1018C>T
NM_007300.3:c.4327C>T
NP_009225.1:p.Arg1443Ter
NP_009230.2:p.Arg340Ter
NP_009231.2:p.Arg1443Ter
LRG_292t1:c.4327C>T
LRG_292:g.135550C>T
LRG_292p1:p.Arg1443Ter
NC_000017.10:g.41234451G>A
NR_027676.1:n.4463C>T
U14680.1:n.4446C>T
p.Arg1443*
p.Arg1443X
p.Arg340*
p.R1443*
U14680.1:n.44446C>T

Nucleotide change:

4446C>T

Protein change:

R1443*; ARG1443TER

Links:

OMIM: 113705.0016; dbSNP: rs41293455

Molecular consequence:

NR_027676.1:n.4463C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_007294.3:c.4327C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:: Hereditary breast and ovarian cancer
Identifiers:: MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000076536	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Pathogenic (Dec 27, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20694749, 11250694, 22798144, 10422801, 19656415, 23233716, 15883839, 16030099, 28492532
SCV000219242	CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 6, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000587391	Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV000588057	Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000591505	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 21, 2013)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9792861, 7894491, 25741868
SCV000605740	Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine)	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 28, 2016)	germline	clinical testing	PubMed (25) [See all records that cite these PMIDs] 16417652, 18680205, 19241424, 8571953, 16030099, 20694749, 7493024, 18821011, 8990217, 21324516, 21203900, 10422801, 9625424, 19863560, 15726418, 17221156, 19656415, 10984458, 15883839, 19329713, 8533757, 22798144, 15951958, 7894491, 24033266
SCV000699132	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 15, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21203900, 7894491, 8571953, 10682662 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Founder populations and their uses for breast cancer genetics.

Neuhausen SL.

Breast Cancer Res. 2000;2(2):77-81. Epub 2000 Feb 7. Review.

PubMed [citation]

PMID:: 11250694
PMCID:: PMC139426

Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network.

Weitzel JN, Clague J, Martir-Negron A, Ogaz R, Herzog J, Ricker C, Jungbluth C, Cina C, Duncan P, Unzeitig G, Saldivar JS, Beattie M, Feldman N, Sand S, Port D, Barragan DI, John EM, Neuhausen SL, Larson GP.

J Clin Oncol. 2013 Jan 10;31(2):210-6. doi: 10.1200/JCO.2011.41.0027. Epub 2012 Dec 10. Erratum in: J Clin Oncol. 2013 May 1;31(13):1702.

PubMed [citation]

PMID:: 23233716
PMCID:: PMC3532393

See all PubMed Citations (31)

Details of each submission

From Invitae, SCV000076536.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Arg1443*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs41293455, ExAC 0.02%). This variant has been reported in many individuals with hereditary breast and ovarian cancer (PMID: 16030099, 23233716, 19656415, 22798144). It is known to be a common cause of disease in the French Canadian population (PMID: 15883839, 10422801, 20694749, 11250694). This variant is also known as 4446C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 17675). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario - The Canadian Open Genetics Repository (COGR), SCV000219242.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587391.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR), SCV000588057.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591505.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), SCV000605740.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (25)

Description

The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers (VÃ©zina 2005, Hall 2009). It has also been identified in 1/6614 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41293455). This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. In addition, functional studies provide some evidence that this variant results in a truncated protein (Caligo 2009). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282327.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000699132.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 30, 2018

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