NM_000059.4(BRCA2):c.7208_7211del (p.Thr2403fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 14, 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:: RCV000215912.14

Allele description [Variation Report for NM_000059.4(BRCA2):c.7208_7211del (p.Thr2403fs)]

NM_000059.4(BRCA2):c.7208_7211del (p.Thr2403fs)

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.7208_7211del (p.Thr2403fs)

HGVS:

NC_000013.10:g.32929193_32929196del
NC_000013.11:g.32355057CCAA[1]
NG_012772.3:g.44578CCAA[1]
NM_000059.4:c.7208_7211delMANE SELECT
NP_000050.3:p.Thr2403fs
LRG_293:g.44578CCAA[1]
NC_000013.10:g.32929193_32929196del
NC_000013.10:g.32929194CCAA[1]
NC_000013.10:g.32929198_32929201del
NC_000013.10:g.32929198_32929201delCCAA
NM_000059.3:c.7208_7211delCCAA
NM_000059.4:c.7208_7211del
U43746.1:n.7436_7439delCCAA

Nucleotide change:

7436del4

Protein change:

T2403fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 7436&base_change=del CCAA; dbSNP: rs80359641

NCBI 1000 Genomes Browser:

rs80359641

Molecular consequence:

NM_000059.4:c.7208_7211del - 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
SCV000278774	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 14, 2022)	germline	clinical testing	Citation Link,
SCV004362192	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17513806, 29446198, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278774

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 14, 2022)

germline

clinical testing

Citation Link,

SCV004362192

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 16, 2022)

germline

clinical testing

PubMed (4)
[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

Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes.

Machado PM, Brandão RD, Cavaco BM, Eugénio J, Bento S, Nave M, Rodrigues P, Fernandes A, Vaz F.

J Clin Oncol. 2007 May 20;25(15):2027-34.

PubMed [citation]

PMID:: 17513806

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, et al.

Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29446198
PMCID:: PMC5903938

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000278774.8

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

Description

The c.7208_7211delCCAA pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 7208 to 7211, causing a translational frameshift with a predicted alternate stop codon (p.T2403Kfs*65). This pathogenic mutation has been reported in two unrelated Portuguese families affected with breast cancer (Machado PM et al. J Clin Oncol. 2007 May 20;25(15):2027-34). 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, SCV004362192.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant deletes 4 nucleotides in exon 14 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 individuals with a personal or family history of breast or ovarian cancer (PMID: 17513806, 29446198, 33471991; Leiden Open Variation Database DB-ID BRCA2_005141). 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: May 26, 2024

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