NM_000059.4(BRCA2):c.5351dup (p.Asn1784fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 20, 2023
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:: RCV000131977.22

Allele description [Variation Report for NM_000059.4(BRCA2):c.5351dup (p.Asn1784fs)]

NM_000059.4(BRCA2):c.5351dup (p.Asn1784fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.5351dup (p.Asn1784fs)

HGVS:

NC_000013.11:g.32339706dup
NG_012772.3:g.29227dup
NM_000059.4:c.5351dupMANE SELECT
NM_000059.4:c.5351dupA
NP_000050.3:p.Asn1784fs
LRG_293t1:c.5351dup
LRG_293:g.29227dup
NC_000013.10:g.32913836_32913837insA
NC_000013.10:g.32913843dup
NM_000059.3:c.5351dup
NM_000059.3:c.5351dupA
NM_000059.4:c.5351dup
U43746.1:n.5579_5580insA
p.N1784KFS*3
p.N1784KfsX3

Nucleotide change:

5579insA

Protein change:

N1784fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5579&base_change=ins A; dbSNP: rs80359507

NCBI 1000 Genomes Browser:

rs80359507

Molecular consequence:

NM_000059.4:c.5351dup - 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
SCV000187035	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 13, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10550133, 10638982, 10699917, 16683254, 21232165, 22006311, 23199084, 25863477, 29084914, 29335924, 9585613 Citation Link,
SCV000292171	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9585613, 10638982, 11597388, 21232165, 22006311, 25863477, 29084914, 29335924, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187035

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 13, 2021)

germline

clinical testing

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

Citation Link,

SCV000292171

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

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

Citations

PubMed

Survival in hereditary breast cancer associated with germline mutations of BRCA2.

Verhoog LC, Brekelmans CT, Seynaeve C, Dahmen G, van Geel AN, Bartels CC, Tilanus-Linthorst MM, Wagner A, Devilee P, Halley DJ, van den Ouweland AM, Meijers-Heijboer EJ, Klijn JG.

J Clin Oncol. 1999 Nov;17(11):3396-402.

PubMed [citation]

PMID:: 10550133

Detection of BRCA1 and BRCA2 mutations in breast cancer families by a comprehensive two-stage screening procedure.

Spitzer E, Abbaszadegan MR, Schmidt F, Hauser A, Buwitt U, Lauter FR, Pötschick K, Krocker J, Elling D, Grosse R.

Int J Cancer. 2000 Feb 15;85(4):474-81.

PubMed [citation]

PMID:: 10699917

See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000187035.8

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

Description

The c.5351dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 5351, causing a translational frameshift with a predicted alternate stop codon (p.N1784Kfs*3). This mutation has been reported in multiple families with breast and/or ovarian cancer (Verhoog LC et al. J. Clin. Oncol. 1999 Nov;17:3396-402; Peelen T et al. Br. J. Cancer. 2000 Jan;82:151-6; Spitzer E et al. Int. J. Cancer. 2000 Feb;85:474-81; van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168:745-753), and has been described as a Dutch founder mutation based on haplotype analysis (Neuhausen SL et al. Am. J. Hum. Genet. 1998 Jun;62:1381-8; Janaviius R. EPMA J. 2010 Sep;1:397-412). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 5579insA and 5573insA 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, SCV000292171.6

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

Description

This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5579insA and 5573insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9585613, 10638982, 11597388, 21232165, 22006311, 25863477, 29084914, 29335924) and is reported as a founder mutation in the Netherlands (PMID: 9585613, 11597388). 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

Last Updated: Nov 3, 2024

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