NM_000059.4(BRCA2):c.7913_7917del (p.Ala2637_Phe2638insTer) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 16, 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:: RCV000131090.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.7913_7917del (p.Ala2637_Phe2638insTer)]

NM_000059.4(BRCA2):c.7913_7917del (p.Ala2637_Phe2638insTer)

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.7913_7917del (p.Ala2637_Phe2638insTer)

Other names:

8138del5

HGVS:

NC_000013.10:g.32936764_32936768del
NC_000013.11:g.32362630_32362634del
NG_012772.3:g.52151_52155del
NM_000059.4:c.7913_7917delMANE SELECT
NP_000050.3:p.Ala2637_Phe2638insTer
LRG_293:g.52151_52155del
NC_000013.10:g.32936764_32936768del
NC_000013.10:g.32936767_32936771del
NC_000013.10:g.32936767_32936771del
NC_000013.10:g.32936767_32936771delTTCCT
NM_000059.3:c.7910_7914del
NM_000059.3:c.7913_7917delTTCCT
NM_000059.4:c.7913_7917del
NM_000059.4:c.7913_7917delTTCCT
U43746.1:n.8138_8142delCCTTT
U43746.1:n.8141_8145delTTCCT
p.F2638*
p.F2638X
p.Phe2638*
p.Phe2638fs

Nucleotide change:

8141del5

Links:

Breast Cancer Information Core (BIC) (BRCA2): 8138&base_change=del CCTTT; Breast Cancer Information Core (BIC) (BRCA2): 8141&base_change=del TTCCT; dbSNP: rs80359686

NCBI 1000 Genomes Browser:

rs80359686

Molecular consequence:

NM_000059.4:c.7913_7917del - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000186020	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 30, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18489799, 20383589, 22729890, 26843898, 29446198, 31173646, 33471991, 33670479, 8988179, 9667259 Citation Link,
SCV000689078	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20383589, 22729890, 24528374, 26843898, 29446198, 31173646, 33471991, 33670479, 25741868
SCV000787951	True Health Diagnostics	no assertion criteria provided	Pathogenic (Dec 7, 2017)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186020

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 30, 2021)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000689078

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

germline

clinical testing

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

SCV000787951

True Health Diagnostics

no assertion criteria provided

Pathogenic
(Dec 7, 2017)

germline

clinical testing

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

Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer.

Machackova E, Foretova L, Lukesova M, Vasickova P, Navratilova M, Coene I, Pavlu H, Kosinova V, Kuklova J, Claes K.

BMC Cancer. 2008 May 20;8:140. doi: 10.1186/1471-2407-8-140.

PubMed [citation]

PMID:: 18489799
PMCID:: PMC2413254

Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D.

Nat Genet. 1997 Jan;15(1):103-5.

PubMed [citation]

PMID:: 8988179

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000186020.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The c.7913_7917delTTCCT pathogenic mutation (also known as p.F2638*), located in coding exon 16 of the BRCA2 gene, results from a deletion of five nucleotides between positions 7913 and 7917. This changes the amino acid from a phenylalanine to a stop codon within coding exon 16. This mutation has been identified in numerous families with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet., 1997 Jan;15:103-5; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Balabas A et al. Fam Cancer, 2010 Sep;9:267-74; Becker AA et al. Breast Cancer Res. Treat., 2012 Aug;135:167-75; Wojcik P et al. Hered Cancer Clin Pract, 2016 Feb;14:5; Cybulski C et al. Int J Cancer, 2019 12;145:3311-3320; ukomska A et al. Cancers (Basel), 2021 Feb;13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was identified multiple times in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). A Czech founder effect was recognized in one study (Machackova E et al. BMC Cancer 2008 May;8:140). Of note, this alteration is also designated as 8141del5 and 8138del5 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, SCV000689078.4

#	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 5 nucleotides in exon 17 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 8141del5 in the literature. This variant has been reported in more than 10 individuals affected with breast or ovarian cancer (PMID: 20383589, 22729890, 24528374, 26843898, 31173646, 33471991, 33670479) and has been identified in 37 families among the CIMBA participants (PMID: 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

From True Health Diagnostics, SCV000787951.1

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

#	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 13, 2024

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