NM_000059.4(BRCA2):c.6408_6414del (p.Asn2137fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 4, 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:: RCV000166653.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.6408_6414del (p.Asn2137fs)]

NM_000059.4(BRCA2):c.6408_6414del (p.Asn2137fs)

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.6408_6414del (p.Asn2137fs)

HGVS:

NC_000013.10:g.32914898_32914904del
NC_000013.11:g.32340763_32340769del
NG_012772.3:g.30284_30290del
NM_000059.4:c.6408_6414delMANE SELECT
NP_000050.3:p.Asn2137fs
LRG_293:g.30284_30290del
NC_000013.10:g.32914898_32914904del
NC_000013.10:g.32914898_32914904delTTAAATG
NC_000013.10:g.32914900_32914906del
NM_000059.3:c.6408_6414delAAATGTT
NM_000059.4:c.6408_6414del
p.L2136LFS*30

Links:

dbSNP: rs397507851

NCBI 1000 Genomes Browser:

rs397507851

Molecular consequence:

NM_000059.4:c.6408_6414del - 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
SCV000217458	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 22, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20380699, 26360800, 28724667 Citation Link,
SCV000683780	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 4, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20380699, 24549055, 25066507, 26360800, 28724667, 29446198, 32772980, 34680878, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217458

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 22, 2021)

germline

clinical testing

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

Citation Link,

SCV000683780

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 4, 2022)

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

BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia.

Tamboom K, Kaasik K, Aršavskaja J, Tekkel M, Lilleorg A, Padrik P, Metspalu A, Veidebaum T.

Hered Cancer Clin Pract. 2010 Apr 9;8(1):4. doi: 10.1186/1897-4287-8-4.

PubMed [citation]

PMID:: 20380699
PMCID:: PMC2867795

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes.

Castéra L, Krieger S, Rousselin A, Legros A, Baumann JJ, Bruet O, Brault B, Fouillet R, Goardon N, Letac O, Baert-Desurmont S, Tinat J, Bera O, Dugast C, Berthet P, Polycarpe F, Layet V, Hardouin A, Frébourg T, Vaur D.

Eur J Hum Genet. 2014 Nov;22(11):1305-13. doi: 10.1038/ejhg.2014.16. Epub 2014 Feb 19.

PubMed [citation]

PMID:: 24549055
PMCID:: PMC4200427

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000217458.7

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

Description

The c.6408_6414delAAATGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 7 nucleotides at nucleotide positions 6408 to 6414, causing a translational frameshift with a predicted alternate stop codon (p.N2137Kfs*29). This mutations has been reported in an Estonian family affected with breast, ovarian, prostate and gastric cancers, a Danish family with multiple cases of prostate cancer and an individual with both male breast cancer and prostate cancer, and in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Tamboom K et al. Hered Cancer Clin Pract. 2010 Apr 9;8(1):4; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Of note, this alteration is also designated as c.6631delTTAAATG and c.6406_6412del 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, SCV000683780.3

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

Description

This variant deletes 7 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 6636delAAATGTT, c.6406_6412del, and c.6631delTTAAATG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 20380699, 24549055, 25066507, 26360800, 28724667, 32772980, 34680878), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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: Jun 2, 2024

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