NM_000059.4(BRCA2):c.3860del (p.Asn1287fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 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:: RCV000131539.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.3860del (p.Asn1287fs)]

NM_000059.4(BRCA2):c.3860del (p.Asn1287fs)

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.3860del (p.Asn1287fs)

Other names:

4088delA; 4082delA

HGVS:

NC_000013.11:g.32338215del
NG_012772.3:g.27736del
NM_000059.4:c.3860delMANE SELECT
NP_000050.3:p.Asn1287fs
LRG_293:g.27736del
NC_000013.10:g.32912346del
NC_000013.10:g.32912352del
NC_000013.10:g.32912352delA
NC_000013.11:g.32338215delA
NM_000059.3:c.3854_3854delA
NM_000059.3:c.3854delA
NM_000059.3:c.3860delA
NM_000059.4:c.3860del
U43746.1:n.4082delA
U43746.1:n.4088delA
p.Asn1287Ilefs*6
p.N1287IfsX6

Nucleotide change:

4088DELA

Links:

Breast Cancer Information Core (BIC) (BRCA2): 4082&base_change=del A; Breast Cancer Information Core (BIC) (BRCA2): 4088&base_change=del A; dbSNP: rs80359406

NCBI 1000 Genomes Browser:

rs80359406

Molecular consequence:

NM_000059.4:c.3860del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000186537	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Pathogenic (Jul 15, 2013)	germline	clinical testing	Citation Link,
SCV000277411	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 10, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11857748, 18821011, 24156927 Citation Link,
SCV000683586	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12673801, 12942367, 12955716, 18821011, 24156927, 27393621, 29446198, 32438681, 33471991, 34645131, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186537

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Pathogenic
(Jul 15, 2013)

germline

clinical testing

Citation Link,

SCV000277411

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 10, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000683586

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (11)
[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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.

Llort G, Muñoz CY, Tuser MP, Guillermo IB, Lluch JR, Bale AE, Franco MA.

Hum Mutat. 2002 Mar;19(3):307.

PubMed [citation]

PMID:: 11857748

BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland.

Perkowska M, BroZek I, Wysocka B, Haraldsson K, Sandberg T, Johansson U, Sellberg G, Borg A, Limon J.

Hum Mutat. 2003 May;21(5):553-4.

PubMed [citation]

PMID:: 12673801

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000186537.2

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

Description

This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediatedâ€¯mRNAâ€¯decay.â€¯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	1	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV000277411.4

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

Description

The c.3860delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 3860, causing a translational frameshift with a predicted alternate stop codon (p.N1287Ifs*6). This alteration has been reported in multiple breast and/or ovarian cancer families to date (Kanaan Y et al. Hum. Genet. 2003 Oct;113(5):452-60; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Zhang J et al. Breast Cancer Res Treat. 2016 Aug;158(3):455-62; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 4088delA 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, SCV000683586.4

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

Description

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4088delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 16 individuals affected with breast cancer, including 2 male individuals and 1 individual affected with both breast and ovarian cancer (PMID: 12673801, 12942367, 12955716, 27393621, 32438681, 33471991, 34645131, doi: 10.51505/ijmshr.2021.5213). This variant has been identified in many families affected with breast and/or ovarian cancer and has been reported in 29 families among CIMBA participants (PMID: 18821011, 24156927, 29446198). 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 30, 2024

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