NM_000059.4(BRCA2):c.7913_7917del (p.Ala2637_Phe2638insTer) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Sep 8, 2016
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000031708.25

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]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000054315	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Sep 27, 2010)	germline	clinical testing
SCV000147214	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline	clinical testing
SCV000301220	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015))	Pathogenic (Sep 8, 2016)	germline	curation	ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000327761	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000605640	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000785901	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Jan 4, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001434323	Division of Medical Genetics, University of Washington - CSER_CHARM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 9, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002588917	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing
SCV004845570	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18489799, 20383589, 22729890, 23199084, 25741868
SCV005046007	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	not provided	not provided	3	not provided	clinical testing
not provided	germline	yes	3	1	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	36	not provided	108544	not provided	clinical testing, curation
Central/Eastern European, Polish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	4	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

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland.

Balabas A, Skasko E, Nowakowska D, Niwinska A, Blecharz P.

Fam Cancer. 2010 Sep;9(3):267-74. doi: 10.1007/s10689-010-9338-5.

PubMed [citation]

PMID:: 20383589

See all PubMed Citations (5)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000054315.5

#	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	not provided	3	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000147214.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	Central/Eastern European, Polish	1	not provided	not provided	clinical testing	not provided
4	Western European	4	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000301220.2

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

Description

Variant allele predicted to encode a truncated non-functional protein.

#	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 Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000327761.4

#	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	36	not provided

From Department of Medical Genetics, Oslo University Hospital, SCV000605640.3

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000785901.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Medical Genetics, University of Washington - CSER_CHARM, SCV001434323.1

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

Description

This deletion leads to a nonsense variant and the introduction of a premature termination codon. The variant is is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the literature in multiple individuals with breast or ovarian cancer (Balabas 2010, Becker 2012, Couch 2015, Wojcik 2016), and is reported to be a founder variant in the Czech population (Machachkova 2008, Janavicius 2010). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From BRCAlab, Lund University, SCV002588917.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	1	not provided

From All of Us Research Program, National Institutes of Health, SCV004845570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer syndrome and is a known founder mutation (PMID: 20383589, 22729890, 22729890, 18489799, 23199084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV005046007.1

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

Description

PVS1; PM2_supporting; PM5_PTC_Strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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