NM_007294.3(BRCA1):c.1961delA (p.Lys654Serfs) AND Hereditary breast and ovarian cancer syndrome

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

Germline classification:: Conflicting classifications of pathogenicity (8 submissions)
Last evaluated:: Nov 1, 2017
Review status:: criteria provided, conflicting classifications

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:: RCV000047660.9

Allele description

NM_007294.3(BRCA1):c.1961delA (p.Lys654Serfs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_007294.3(BRCA1):c.1961delA (p.Lys654Serfs)

HGVS:

NC_000017.11:g.43093570delT
NG_005905.2:g.124414delA
NM_007294.3:c.1961delA
NM_007298.3:c.787+1174delA
NM_007300.3:c.1961delA
NP_009225.1:p.Lys654Serfs
NP_009231.2:p.Lys654Serfs
LRG_292t1:c.1961delA
LRG_292:g.124414delA
LRG_292p1:p.Lys654Serfs
NC_000017.10:g.41245587delT
NM_007294.3:c.1961_1961delA
NM_007294.3:c.1961del
NR_027676.1:n.2097delA
U14680.1:n.2080delA
p.K654SFS*47
p.Lys654Serfs*47
p.Lys654SerfsX47

Nucleotide change:

2080delA

Links:

Breast Cancer Information Core (BIC) (BRCA1): 2080&base_change=del A; dbSNP: rs80357522

NCBI 1000 Genomes Browser:

rs80357522

Allele Frequency:

0.00001(-)

Molecular consequence:

NM_007294.3:c.1961delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007298.3:c.787+1174delA - intron variant - [Sequence Ontology: SO:0001627]
NR_027676.1:n.2097delA - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000075673	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Pathogenic (Oct 19, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26026974, 23633455, 17645508, 12955716, 7493024, 28492532
SCV000324814	CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000403071	Illumina Clinical Services Laboratory,Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 23633455, 7493024, 12955716, 23479189, 14517958, 17645508, 22798144, 25863477, 16455195, 20727672, 25256238, 11956590, 24884479, 11179017 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000587176	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
SCV000588035	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]
SCV000591357	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000693514	GeneKor MSA,	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000698901	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 6, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14760071, 7493024, 23633455, 21702907, 12955716 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	not provided	not provided	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

BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study.

de Juan I, Palanca S, Domenech A, Feliubadaló L, Segura Á, Osorio A, Chirivella I, de la Hoya M, Sánchez AB, Infante M, Tena I, Díez O, Garcia-Casado Z, Vega A, Teulé À, Barroso A, Pérez P, Durán M, Carrasco E, Juan-Fita MJ, Murria R, Llop M, et al.

Fam Cancer. 2015 Dec;14(4):505-13. doi: 10.1007/s10689-015-9814-z.

PubMed [citation]

PMID:: 26026974

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (19)

Details of each submission

From Invitae, SCV000075673.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change deletes 1 nucleotide from exon 10 of the BRCA1 mRNA (c.1961delA), causing a frameshift at codon 654. This creates a premature translational stop signal (p.Lys654Serfs*47) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with breast, ovarian, and endometrial cancer (PMID: 7493024, 12955716, 17645508, 23633455, 26026974). This variant is also known as 2073delA and 2080delA in the literature. 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, SCV000324814.1

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

Description

Interpretation was last updated within 1 year from 2/16/2016 10:54 AM

#	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		not provided	not provided	not provided	not provided

From Illumina Clinical Services Laboratory,Illumina, SCV000403071.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The c.1961delA (p.Lys654SerfsTer47) variant (also commonly referred to as c.2080delA) results in a frameshift, and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys654SerfsTer47 variant has been identified in a heterozygous state in 29 cases of breast or ovarian cancer (Gayther et al. 1995; Risch et al. 2001; Curci et al. 2002; Diez et al. 2003; Martinez-Ferrandis et al. 2003; Ahn et al. 2007; Kwon et al. 2008; Iyevleva et al. 2010; Kim et al. 2012; Kang et al. 2015; de Juan Jiminez et al. 2013; George et al. 2013; Abugattas et al. 2014; Silva et al. 2014). The variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (Non-Finnish) population of the Exome Aggregation Consortium Project but this is based on one allele so the variant is presumed to be rare. Most variants in the BRCA1 gene that have been shown to be associated with breast and ovarian cancer are frameshift variants resulting in a non-functional protein. Based on the potential impact of frameshift variants and the available evidence, the p.Lys654SerfsTer47 variant is classified as pathogenic for hereditary breast and ovarian cancer syndrome.

#	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), SCV000587176.1

#	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), SCV000588035.1

#	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), SCV000591357.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneKor MSA,, SCV000693514.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000698901.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: The BRCA1 c.1961delA (p.Lys654Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2001dupA, c.2299delA). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121294 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in numerous HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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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