NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (14 submissions)
Last evaluated:: Nov 9, 2023
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:: RCV000031798.30

Allele description [Variation Report for NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)]

NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)

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.9117G>A (p.Pro3039=)

Other names:

P3039P; p.P3039P:CCG>CCA; NM_000059.4(BRCA2):c.9117G>A; p.Pro3039=

HGVS:

NC_000013.11:g.32379913G>A
NG_012772.3:g.69434G>A
NM_000059.4:c.9117G>AMANE SELECT
NP_000050.2:p.Pro3039=
NP_000050.3:p.Pro3039=
LRG_293t1:c.9117G>A
LRG_293:g.69434G>A
LRG_293p1:p.Pro3039=
NC_000013.10:g.32954050G>A
NM_000059.3:c.9117G>A
U43746.1:n.9345G>A
p.P3039P

Nucleotide change:

9345G>A

Links:

dbSNP: rs28897756

NCBI 1000 Genomes Browser:

rs28897756

Molecular consequence:

NM_000059.4:c.9117G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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

Recent activity

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Chrysis sp. MC-2010 28S large subunit ribosomal RNA gene, partial sequence
Chrysis sp. MC-2010 28S large subunit ribosomal RNA gene, partial sequence
gi|300676538|gb|GU213972.1|

Nucleotide
Streptococcus pneumoniae strain 2842STDY5753486, whole genome shotgun sequence
Streptococcus pneumoniae strain 2842STDY5753486, whole genome shotgun sequence
gi|1005637892|ref|NZ_FDMI01000007.1

Nucleotide
aliphatic sulfonate ABC transporter substrate-binding protein SsuA [Escherichia ...
aliphatic sulfonate ABC transporter substrate-binding protein SsuA [Escherichia coli]
gi|447149010|ref|WP_001226266.1|

Protein
Uncultured sulfate-reducing bacterium clone OTU-5 dissimilatory sulfite reductas...
Uncultured sulfate-reducing bacterium clone OTU-5 dissimilatory sulfite reductase beta subunit (dsrB) gene, partial cds
gi|161347456|gb|EU258880.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000054406	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Aug 31, 2013)	germline	clinical testing
SCV000147546	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (Feb 20, 2004)	germline, unknown	clinical testing
SCV000328057	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,
SCV000488254	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Feb 3, 2016)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22505045, 23451180, 22632462, 21324516, 10638982 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000575743	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 18, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000605690	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000733331	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000743359	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Oct 10, 2014)	germline	clinical testing	Citation Link,
SCV000744555	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Sep 21, 2015)	germline	clinical testing	Citation Link,
SCV000839919	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001139248	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001251960	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002588935	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing
SCV004846127	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 18821011, 22505045, 22798144, 23451180, 24156927, 24249303, 25382762, 25480878, 25556971, 25948282, 26026974, 27000661, 27060066, 28477318, 28724667, 30287823, 31843900, 32393398, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	9	not provided	not provided	9	not provided	clinical testing
not provided	germline	unknown	4	66	not provided	108544	not provided	clinical testing
not provided	germline	yes	9	1	not provided	not provided	not provided	clinical testing
not provided	not provided	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
African	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Caucasian	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
Western European, Italian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes.

Acedo A, Sanz DJ, Durán M, Infante M, Pérez-Cabornero L, Miner C, Velasco EA.

Breast Cancer Res. 2012 May 25;14(3):R87.

PubMed [citation]

PMID:: 22632462
PMCID:: PMC3446350

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.

Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, Fan I, Bradley L, Shaw PA, Narod SA.

Gynecol Oncol. 2011 May 1;121(2):353-7. doi: 10.1016/j.ygyno.2011.01.020. Epub 2011 Feb 15.

PubMed [citation]

PMID:: 21324516

See all PubMed Citations (22)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000054406.5

#	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	9	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000147546.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	African	2	not provided	not provided	clinical testing	not provided
4	Ashkenazi	1	not provided	not provided	clinical testing	not provided
5	Caucasian	1	not provided	not provided	clinical testing	not provided
6	Western European	4	not provided	not provided	clinical testing	not provided
7	Western European, Italian	1	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		4	not provided	not provided	not provided
2	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided
7	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000328057.4

#	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	66	not provided

From Counsyl, SCV000488254.2

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

#	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 Fulgent Genetics, Fulgent Genetics, SCV000575743.1

#	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 Department of Medical Genetics, Oslo University Hospital, SCV000605690.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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		5	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733331.1

#	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	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743359.1

#	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	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV000744555.1

#	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	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839919.1

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

Description

The c.9117G>A (p.Pro3039Pro) variant in the BRCA2 gene has been detected in multiple patients and families with breast and/or ovarian cancer [PMID 10638982 reported as 3398delAAAAG, 27000661] and a cohort of patients with prostate cancer [PMID 23035815, reported as c.9117 G>A (p.Val2985fs)]. The nucleotide position 9117 is the last nucleotide of exon 23. Several in vitro assays showed that the change leads aberrant splicing and the skipping of exon 23 [PMID 22505045, 23451180]. This variant is thus predicted to result in a loss of function of the protein. This variant has not been reported in the ExAC database. This variant thus 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 Mendelics, SCV001139248.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV001251960.1

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

From BRCAlab, Lund University, SCV002588935.1

#	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, SCV004846127.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (19)

Description

This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 chromosomes 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	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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