NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs) AND Hereditary breast ovarian cancer syndrome

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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000043880.22

Allele description

NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs)

Other names:

2001del4; 2000del4; 2000_2003delTTTA

HGVS:

NC_000013.10:g.32907383_32907386del
NC_000013.11:g.32333247TTAT[1]
NG_012772.3:g.22768TTAT[1]
NM_000059.4:c.1773_1776delMANE SELECT
NP_000050.3:p.Ile591fs
LRG_293:g.22768TTAT[1]
NC_000013.10:g.32907383_32907386del
NC_000013.10:g.32907384TTAT[1]
NC_000013.10:g.32907388_32907391del
NC_000013.10:g.32907388_32907391delTTAT
NM_000059.3:c.1773_1776delTTAT
NM_000059.4:c.1773_1776delTTAT
U43746.1:n.2000_2003delTTTA
U43746.1:n.2001_2004delTTAT
p.I591MfsX22
p.Ile591Metfs*22
U43746.1:n.2001_2004delTATT

Protein change:

I591fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 2000&base_change=del TTTA; Breast Cancer Information Core (BIC) (BRCA2): 2001&base_change=del TATT; Breast Cancer Information Core (BIC) (BRCA2): 2001&base_change=del TTAT; dbSNP: rs80359304

NCBI 1000 Genomes Browser:

rs80359304

Molecular consequence:

NM_000059.4:c.1773_1776del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071893	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20104584, 12942367, 18393245, 22923021, 28492532
SCV000587609	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
SCV001623181	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000071893

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000587609

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

SCV001623181

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 18, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases.

Kanaan Y, Kpenu E, Utley K, Adams-Campbell L, Dunston GM, Brody LC, Broome C.

Hum Genet. 2003 Oct;113(5):452-60. Epub 2003 Aug 26.

PubMed [citation]

PMID:: 12942367

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000071893.12

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

Description

This sequence change creates a premature translational stop signal (p.Ile591Metfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12942367, 18393245, 22923021). This variant is also known as 2001delTTAT. ClinVar contains an entry for this variant (Variation ID: 51190). 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 Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587609.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623181.1

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

Description

Variant summary: BRCA2 c.1773_1776delTTAT (p.Ile591MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 248932 control chromosomes. c.1773_1776delTTAT has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, 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 16, 2024

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