NM_000059.4(BRCA2):c.3865_3868del (p.Lys1289fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 7, 2022
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:: RCV000216772.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.3865_3868del (p.Lys1289fs)]

NM_000059.4(BRCA2):c.3865_3868del (p.Lys1289fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.3865_3868del (p.Lys1289fs)

Other names:

NP_000050.3:p.Lys1289AlafsTer3

HGVS:

NC_000013.10:g.32912354_32912357del
NC_000013.11:g.32338220_32338223del
NG_012772.3:g.27741_27744del
NM_000059.4:c.3865_3868delMANE SELECT
NP_000050.3:p.Lys1289fs
LRG_293:g.27741_27744del
NC_000013.10:g.32912354_32912357del
NC_000013.10:g.32912357_32912360del
NC_000013.10:g.32912357_32912360delAAAT
NM_000059.3:c.3862_3865del
NM_000059.3:c.3865_3868delAAAT
NM_000059.4:c.3865_3868del
U43746.1:n.4093_4096del4
U43746.1:n.4093_4096delAAAT
p.Lys1289Alafs*3

Nucleotide change:

4093del4

Links:

Breast Cancer Information Core (BIC) (BRCA2): 4093&base_change=del 4; dbSNP: rs80359412

NCBI 1000 Genomes Browser:

rs80359412

Molecular consequence:

NM_000059.4:c.3865_3868del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274990	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 7, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11102978, 12402332, 20104584, 22729890, 24578176, 24728189, 28993434, 29446198, 30093976, 32072338, 32832836 Citation Link,
SCV000683587	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 14, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20104584, 24728189, 28993434, 29797126, 33471991, 25741868
SCV002533828	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jan 25, 2022)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 33646313, 20104584, 28993434, 30875412, 30093976, 29446198 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274990

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 7, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link,

SCV000683587

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 14, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002533828

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jan 25, 2022)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

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, curation

Citations

PubMed

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer.

Shiri-Sverdlov R, Oefner P, Green L, Baruch RG, Wagner T, Kruglikova A, Haitchick S, Hofstra RM, Papa MZ, Mulder I, Rizel S, Bar Sade RB, Dagan E, Abdeen Z, Goldman B, Friedman E.

Hum Mutat. 2000 Dec;16(6):491-501.

PubMed [citation]

PMID:: 11102978

A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families.

Phelan CM, Kwan E, Jack E, Li S, Morgan C, Aubé J, Hanna D, Narod SA.

Hum Mutat. 2002 Nov;20(5):352-7.

PubMed [citation]

PMID:: 12402332

See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV000274990.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The c.3865_3868delAAAT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3865 to 3868, causing a translational frameshift with a predicted alternate stop codon (p.K1289Afs*3). This mutation has been reported in multple breast and/or ovarian cancer patients of varying ethnicities (Shiri-Sverdlov R et al. Hum. Mutat. 2000 Dec;16:491-501; Phelan CM et al. Hum Mutat, 2002 Nov;20:352-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Kang PC et al. Breast Cancer Res. Treat. 2014 Apr;144:635-42; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; hen L et al. Breast Cancer Res Treat, 2020 Apr;180:759-766). This mutation was also identified in a cohort of 3579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). Of note, this alteration is also designated as 4093del4 and 4093delAAAT in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000683587.3

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

Description

This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least four individuals affected with breast or ovarian cancer and also in two unaffected individuals (PMID: 20104584, 24728189, 28993434, 29797126, 33471991; Leiden Open Variation Database DB-ID BRCA2_001167). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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

From Sema4, Sema4, SCV002533828.1

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

#	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: Oct 20, 2024

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