NM_000059.4(BRCA2):c.7024C>T (p.Gln2342Ter) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (9 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:: RCV000077396.11

Allele description [Variation Report for NM_000059.4(BRCA2):c.7024C>T (p.Gln2342Ter)]

NM_000059.4(BRCA2):c.7024C>T (p.Gln2342Ter)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7024C>T (p.Gln2342Ter)

HGVS:

NC_000013.11:g.32354877C>T
NG_012772.3:g.44398C>T
NM_000059.4:c.7024C>TMANE SELECT
NP_000050.2:p.Gln2342Ter
NP_000050.3:p.Gln2342Ter
LRG_293t1:c.7024C>T
LRG_293:g.44398C>T
LRG_293p1:p.Gln2342Ter
NC_000013.10:g.32929014C>T
NM_000059.3:c.7024C>T
U43746.1:n.7252C>T
p.Gln2342*

Nucleotide change:

7252C>T

Protein change:

Q2342*

Links:

dbSNP: rs80358928

NCBI 1000 Genomes Browser:

rs80358928

Molecular consequence:

NM_000059.4:c.7024C>T - 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
SCV000109193	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Nov 7, 2013)	germline	clinical testing
SCV000147003	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (Feb 20, 2004)	germline	clinical testing
SCV000301121	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,
SCV000327580	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,
SCV000605672	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]
SCV000778598	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 23, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000785707	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Nov 8, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19787003, 25525159, 28637432, 25452441 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001434855	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 12, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046891	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 24, 2023)	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	not provided	3	not provided	not provided	3	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	1	not provided	clinical testing, research
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	3	not provided	not provided	not provided	clinical testing, curation
Western European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast cancer in a BRCA2 mutation carrier with a history of prostate cancer.

Panchal S, Shachar O, O'Malley F, Crystal P, Escallon J, Crook J, Bane A, Bordeleau L.

Nat Rev Clin Oncol. 2009 Oct;6(10):604-7. doi: 10.1038/nrclinonc.2009.116.

PubMed [citation]

PMID:: 19787003

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

See all PubMed Citations (5)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000109193.3

#	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), SCV000147003.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	Western European	2	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		2	not provided	not provided	not provided

From Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000301121.2

#	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, SCV000327580.4

#	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	3	not provided

From Department of Medical Genetics, Oslo University Hospital, SCV000605672.3

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha, SCV000778598.1

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

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

From Counsyl, SCV000785707.2

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

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434855.1

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

Description

This rare nonsense variant c.7024C>T, (p.Gln2342Ter) in the BRCA2 gene is rare in public databases (seen once in Gnomad) and is predicted to result in a loss of function of BRCA2. Loss of function variants in BRCA1 are known to be pathogenic for breast cancer. This variant has been observed in multiple unrelated individuals with breast and other cancers (PMID 11836363, 12491487, 19787003). Family history was consistent with mode of iheritance of breast cancer in one family (PMID 19787003). Based upon the above evidence, this c.7024C>T, (p.Gln2342*) variant in BRCA2 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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004046891.1

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

Description

This sequence change creates a premature translational stop signal (p.Gln2342*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80358928, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19787003, 28637432). ClinVar contains an entry for this variant (Variation ID: 52250). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 8, 2024

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