VCV000038215.77 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

36 submissions

34 submitters

12 conditions

Reviewed by expert panel

Pathogenic

Jun 2024 by ClinGen ENIGMA… FDA Recognized Database

for BRCA2-related cancer predisposition

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 38215 Accession: VCV000038215.77

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32379913 (GRCh38) [ NCBI UCSC ] 13: 32954050 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 27, 2014	Sep 16, 2024	Jun 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9117G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Pro3039=	synonymous
NC_000013.11:g.32379913G>A
NC_000013.10:g.32954050G>A
NG_012772.3:g.69434G>A
LRG_293:g.69434G>A
LRG_293t1:c.9117G>A	LRG_293p1:p.Pro3039=
U43746.1:n.9345G>A

... more HGVS ... less HGVS

Protein change

Other names

P3039P
p.P3039P:CCG>CCA
NM_000059.4(BRCA2):c.9117G>A
p.Pro3039=
9345G>A

Canonical SPDI

NC_000013.11:32379912:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA025994 dbSNP: rs28897756 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18967	19126

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (14)	reviewed by expert panel	Nov 9, 2023	RCV000031798.30
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jun 17, 2024	RCV000074560.32
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 19, 2023	RCV000131039.19
Hereditary breast ovarian cancer syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000045725.32
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Tracheoesophageal fistula Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	May 18, 2017	RCV000515207.10
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763330.10
Breast-ovarian cancer, familial, susceptibility to, 2 Hereditary breast ovarian cancer syndrome	Pathogenic (1)	no assertion criteria provided	Sep 1, 2019	RCV001171453.11
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 9, 2021	RCV001554310.9
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV003473227.2
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310189.9
BRCA2-related cancer predisposition	Pathogenic (1)	reviewed by expert panel	Jun 11, 2024	RCV004566785.1
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162286.8
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 11, 2024)	reviewed by expert panel (CSpec BRCA1/2ACMG Rules Specifications V1.0) Method: curation	BRCA2-related cancer predisposition (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004101443.3 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f116122-06ef-40a9-934f-9c6654fe75f9 Comment: The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer … (more) The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong). (less)
Pathogenic (May 25, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839919.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 08, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494420.2 First in ClinVar: Feb 04, 2017 Last updated: Nov 11, 2020	Publications: PubMed (12) PubMed: 21990134‚ 17924331‚ 11802209‚ 22505045‚ 23451180‚ 22632462‚ 22923021‚ 17011978‚ 24249303‚ 10638982‚ 28477318‚ 27000661 Comment: Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more) Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5' splicing donor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (e.g. Bonatti_2006, Acedo_2012, Houdayer_2012, Colombo_2013). The variant allele was found at a frequency of 4e-06 in 248378 control chromosomes. c.9117G>A has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peelen_2000, Meindl_2002, Bonatti_2006, Novakovic_2012, Nakamura_2013, Corman_2016, Barrios_2017). These data indicate that the variant is very likely to be associated with disease. 17 other ClinVar submitters, including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 01, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532009.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BRCA2 c.9117G>A (p.P3039=) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancers (PMID: 25186627, 28477318, 28724667, 28825054, 29176636, … (more) The BRCA2 c.9117G>A (p.P3039=) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancers (PMID: 25186627, 28477318, 28724667, 28825054, 29176636, 32393398). This variant is also known as 9345G>A in the literature.Functional studies have shown that this variant alters splicing leading to a skipping of exon 23 and creation of a premature stop codon at amino acid 2985 (PMID: 10638982, 17011978, 23451180 ). At this location, this is predicted to result in absent protein (loss of function). Loss of function variants in BRCA2 are known to be pathogenic (PMID: 29446198). This variant was observed in 1/111660 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 38215). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (10) PubMed: 25186627‚ 28477318‚ 28724667‚ 28825054‚ 29176636‚ 32393398‚ 10638982‚ 17011978‚ 23451180‚ 29446198
Pathogenic (Jun 17, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000108645.19 First in ClinVar: Dec 10, 2013 Last updated: Sep 16, 2024	Comment: Alters the last nucleotide of the exon and has been demonstrated to cause aberrant splicing, predicted to result in a null allele in a gene … (more) Alters the last nucleotide of the exon and has been demonstrated to cause aberrant splicing, predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 10638982, 17011978, 22632462, 23451180, 25382762); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 17924331, 21990134); Published functional studies demonstrate a damaging effect: reduced homology-directed repair (HDR) activity (PMID: 32398771); Observed in multiple breast/ovarian cancer families (PMID: 10638982, 17148771, 22923021, 24156927, 26026974, 28477318, 28724667); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9345G>A; This variant is associated with the following publications: (PMID: 22798144, 17011978, 22505045, 22632462, 26026974, 25948282, 33309985, 36367610, 35142179, 36881271, 36243179, 34887416, 36113475, 37310942, 35864222, 28477318, 29084914, 34413315, 38075165, 29922827, 28888541, 31447099, 32658311, 17924331, 23451180, 23035815, 22923021, 17148771, 20507642, 22217648, 18375895, 10638982, 9133456, 21324516, 18821011, 25556971, 28008555, 24156927, 27000661, 21702907, 28740454, 28873162, 27271530, 25186627, 28724667, 29805665, 29907814, 29339979, 28825054, 30702160, 31957001, 31143373, 29176636, 31825140, 31892343, 31723001, 35273153, 34645131, 33804961, 34808016, 32338768, 32393398, 32853339, 30787465, 36988593, 36000185, 25382762, 21990134, 32398771) (less)
Pathogenic (Sep 18, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000575743.1 First in ClinVar: May 07, 2017 Last updated: May 07, 2017
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Tracheoesophageal fistula Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611181.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894007.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139248.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000328057.4 First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022
Pathogenic (Nov 02, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605690.3 First in ClinVar: Sep 28, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 5
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004027489.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (Sep 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021530.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Apr 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000537643.3 First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024	Publications: PubMed (18) PubMed: 18821011‚ 22505045‚ 22798144‚ 23451180‚ 24156927‚ 24249303‚ 25382762‚ 25480878‚ 25556971‚ 25948282‚ 26026974‚ 27000661‚ 27060066‚ 28477318‚ 28724667‚ 30287823‚ 31843900‚ 32393398 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211922.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 10, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743359.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744555.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251960.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Pathogenic (Nov 03, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450340.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 1
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499784.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Feb 03, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488254.2 First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 22505045‚ 23451180‚ 22632462‚ 21324516‚ 10638982
Pathogenic (Aug 06, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296758.6 First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024	Publications: PubMed (24) PubMed: 26295337‚ 18375895‚ 10638982‚ 22632462‚ 17924331‚ 21990134‚ 23451180‚ 22505045‚ 23035815‚ 17011978‚ 28724667‚ 28477318‚ 27060066‚ 25186627‚ 28825054‚ 29176636‚ 29907814‚ 30702160‚ 30787465‚ 31143373‚ 31447099‚ 31825140‚ 32658311‚ 32853339 Comment: It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), … (more) It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), 21990134 (2012), 23451180 (2013), 28724667 (2017)). Furthermore, experimental studies have shown that the variant causes the skipping of exon 23, resulting in premature termination in protein synthesis (PMID: 22505045 (2012), 22632462 (2012), 23451180 (2013), and 27060066 (2016)). Based on the available information, the variant is classified as pathogenic. (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000073738.15 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (15) PubMed: 28492532‚ 10638982‚ 17011978‚ 17148771‚ 22923021‚ 23035815‚ 26026974‚ 17924331‚ 21990134‚ 17576681‚ 9536098‚ 22505045‚ 22632462‚ 23451180‚ 25382762 Comment: This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with breast, ovarian, or prostate cancer (PMID: 10638982, 17011978, 17148771, 22923021, 23035815, 26026974). This variant is also known as 9345G>A. ClinVar contains an entry for this variant (Variation ID: 38215). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and introduces a premature termination codon (PMID: 22505045, 22632462, 23035815, 23451180, 25382762; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846127.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (18) PubMed: 18821011‚ 22505045‚ 22798144‚ 23451180‚ 24156927‚ 24249303‚ 25382762‚ 25480878‚ 25556971‚ 25948282‚ 26026974‚ 27000661‚ 27060066‚ 28477318‚ 28724667‚ 30287823‚ 31843900‚ 32393398 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 4
Pathogenic (Jun 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848273.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (8) PubMed: 10638982‚ 22632462‚ 22505045‚ 23035815‚ 23451180‚ 26026974‚ 27000661‚ 29084914 Comment: The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, … (more) The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, Willems-Jones 2012 PMID: 23035815, de Juan 2015 PMID: 26026974, Corman 2016 PMID: 27000661, Labidi-Galy 2018 PMID: 29084914). It has also been identified in 1/111660 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant has also been identified in ClinVar (Variation ID: 38215). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, and both in vitro studies and testing of patient RNA have shown that this variant results in exon skipping, which is predicted to lead to an absent or truncated protein (Peelen 2000 PMID: 10638982, Acedo 2012 PMID: 22632462, Houdayer 2012 PMID: 22505045, Colombo 2013 PMID: 23451180). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.9117G>T, resulting in the same synonymous change and predicted splicing impact has also been identified in individuals with BRCA2-related cancers. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS3, PM2, PS4. (less)
Pathogenic (Apr 08, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000185969.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (30) PubMed: 10638982‚ 11897832‚ 16683254‚ 17011978‚ 17148771‚ 17924331‚ 18375895‚ 18821011‚ 19016756‚ 19656164‚ 20406929‚ 21324516‚ 21990134‚ 22217648‚ 22505045‚ 22632462‚ 22798144‚ 22923021‚ 23035815‚ 24156927‚ 24249303‚ 25382762‚ 25480878‚ 25556971‚ 25948282‚ 26026974‚ 27000661‚ 27271530‚ 28477318‚ 28724667 Comment: The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at … (more) The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9117. This nucleotide substitution does not change the at codon 3039. However, this change occurs in the last base pair of coding exon 22 and has been shown to cause aberrant RNA transcripts due to exon skipping that results in a frameshift at codon 2985 and premature protein truncation (V2985Gfs*3) (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Acedo A et al. Hum. Mutat. 2015 Feb;36:210-21). This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Hamann U et al. J. Med. Genet. 2002 Mar;39:E12; Spurdle AB et al. J. Clin. Oncol. 2008 Apr;26:1657-63; Fong PC et al. J. Clin. Oncol. 2010 May;28:2512-9; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Takahashi M et al. Breast Cancer. 2017 Mar;24(2):336-340; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration has also been reported in a male with aggressive prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6) and in biological males with breast cancer (de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Corman V et al. Endocr. Relat. Cancer. 2016 May;23:391-7). Of note, this mutation is also designated as 9345G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Aug 31, 2013)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000054406.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014
Pathogenic (Feb 20, 2004)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline, unknown	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147546.2 First in ClinVar: Apr 01, 2014 Last updated: Sep 27, 2014	Observation 1: Number of individuals with the variant: 4 Observation 2: Number of individuals with the variant: 2 Ethnicity/Population group: African Observation 3: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi Observation 4: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Italy Observation 5: Number of individuals with the variant: 4 Ethnicity/Population group: Western European Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Italian Observation 7: Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733331.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Sep 01, 2019)	no assertion criteria provided Method: research	Hereditary breast and ovarian cancer syndrome Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	King Laboratory, University of Washington Accession: SCV001251364.1 First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020 Comment: Transcript analysis by cBROCA	Publications: PubMed (1) PubMed: 31843900
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906367.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588935.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587988.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (Aug 09, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001774869.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: Diagnosis: Breast cancer Pathology: Invasive ductal breast carcinoma IHC: ER:+, PR:+, HER2:- Age: 40-49 years Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955049.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758412.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
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Comment:

The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong).

Comment:

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.

Comment:

Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5' splicing donor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (e.g. Bonatti_2006, Acedo_2012, Houdayer_2012, Colombo_2013). The variant allele was found at a frequency of 4e-06 in 248378 control chromosomes. c.9117G>A has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peelen_2000, Meindl_2002, Bonatti_2006, Novakovic_2012, Nakamura_2013, Corman_2016, Barrios_2017). These data indicate that the variant is very likely to be associated with disease. 17 other ClinVar submitters, including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Alters the last nucleotide of the exon and has been demonstrated to cause aberrant splicing, predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 10638982, 17011978, 22632462, 23451180, 25382762); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 17924331, 21990134); Published functional studies demonstrate a damaging effect: reduced homology-directed repair (HDR) activity (PMID: 32398771); Observed in multiple breast/ovarian cancer families (PMID: 10638982, 17148771, 22923021, 24156927, 26026974, 28477318, 28724667); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9345G>A; This variant is associated with the following publications: (PMID: 22798144, 17011978, 22505045, 22632462, 26026974, 25948282, 33309985, 36367610, 35142179, 36881271, 36243179, 34887416, 36113475, 37310942, 35864222, 28477318, 29084914, 34413315, 38075165, 29922827, 28888541, 31447099, 32658311, 17924331, 23451180, 23035815, 22923021, 17148771, 20507642, 22217648, 18375895, 10638982, 9133456, 21324516, 18821011, 25556971, 28008555, 24156927, 27000661, 21702907, 28740454, 28873162, 27271530, 25186627, 28724667, 29805665, 29907814, 29339979, 28825054, 30702160, 31957001, 31143373, 29176636, 31825140, 31892343, 31723001, 35273153, 34645131, 33804961, 34808016, 32338768, 32393398, 32853339, 30787465, 36988593, 36000185, 25382762, 21990134, 32398771)

Comment:

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.

Comment:

It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), 21990134 (2012), 23451180 (2013), 28724667 (2017)). Furthermore, experimental studies have shown that the variant causes the skipping of exon 23, resulting in premature termination in protein synthesis (PMID: 22505045 (2012), 22632462 (2012), 23451180 (2013), and 27060066 (2016)). Based on the available information, the variant is classified as pathogenic.

Comment:

This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with breast, ovarian, or prostate cancer (PMID: 10638982, 17011978, 17148771, 22923021, 23035815, 26026974). This variant is also known as 9345G>A. ClinVar contains an entry for this variant (Variation ID: 38215). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and introduces a premature termination codon (PMID: 22505045, 22632462, 23035815, 23451180, 25382762; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, Willems-Jones 2012 PMID: 23035815, de Juan 2015 PMID: 26026974, Corman 2016 PMID: 27000661, Labidi-Galy 2018 PMID: 29084914). It has also been identified in 1/111660 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant has also been identified in ClinVar (Variation ID: 38215). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, and both in vitro studies and testing of patient RNA have shown that this variant results in exon skipping, which is predicted to lead to an absent or truncated protein (Peelen 2000 PMID: 10638982, Acedo 2012 PMID: 22632462, Houdayer 2012 PMID: 22505045, Colombo 2013 PMID: 23451180). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.9117G>T, resulting in the same synonymous change and predicted splicing impact has also been identified in individuals with BRCA2-related cancers. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS3, PM2, PS4.

Comment:

The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9117. This nucleotide substitution does not change the at codon 3039. However, this change occurs in the last base pair of coding exon 22 and has been shown to cause aberrant RNA transcripts due to exon skipping that results in a frameshift at codon 2985 and premature protein truncation (V2985Gfs*3) (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Acedo A et al. Hum. Mutat. 2015 Feb;36:210-21). This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Hamann U et al. J. Med. Genet. 2002 Mar;39:E12; Spurdle AB et al. J. Clin. Oncol. 2008 Apr;26:1657-63; Fong PC et al. J. Clin. Oncol. 2010 May;28:2512-9; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Takahashi M et al. Breast Cancer. 2017 Mar;24(2):336-340; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration has also been reported in a male with aggressive prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6) and in biological males with breast cancer (de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Corman V et al. Endocr. Relat. Cancer. 2016 May;23:391-7). Of note, this mutation is also designated as 9345G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.	Akcay IM	International journal of cancer	2021	PMID: 32658311
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay.	Sirisena N	Breast cancer research : BCR	2020	PMID: 32393398
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.	Gao X	Human mutation	2020	PMID: 31825140
Characterization of splice-altering mutations in inherited predisposition to cancer.	Casadei S	Proceedings of the National Academy of Sciences of the United States of America	2019	PMID: 31843900
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Analysis of clinical characteristics of breast cancer patients with the Japanese founder mutation BRCA1 L63X.	Yoshida R	Oncotarget	2019	PMID: 31143373
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.	Bhaskaran SP	International journal of cancer	2019	PMID: 30702160
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.	Arai M	Journal of human genetics	2018	PMID: 29176636
Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.	Labidi-Galy SI	Clinical cancer research : an official journal of the American Association for Cancer Research	2018	PMID: 29084914
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.	Abida W	JCO precision oncology	2017	PMID: 28825054
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.	Gabaldó Barrios X	Familial cancer	2017	PMID: 28477318
OLA1 gene sequencing in patients with BRCA1/2 mutation-negative suspected hereditary breast and ovarian cancer.	Takahashi M	Breast cancer (Tokyo, Japan)	2017	PMID: 27271530
Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples.	Fackenthal JD	Journal of medical genetics	2016	PMID: 27060066
Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation.	Corman V	Endocrine-related cancer	2016	PMID: 27000661
BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study.	de Juan I	Familial cancer	2015	PMID: 26026974
New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing.	Kluska A	BMC medical genomics	2015	PMID: 25948282
Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer.	Trujillano D	The Journal of molecular diagnostics : JMD	2015	PMID: 25556971
Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer.	Wang C	Annals of oncology : official journal of the European Society for Medical Oncology	2015	PMID: 25480878
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons.	Acedo A	Human mutation	2015	PMID: 25382762
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
Prevalence and differentiation of hereditary breast and ovarian cancers in Japan.	Nakamura S	Breast cancer (Tokyo, Japan)	2015	PMID: 24249303
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.	Tea MK	Maturitas	2014	PMID: 24156927
Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations.	Colombo M	PloS one	2013	PMID: 23451180
High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer.	Willems-Jones A	BJU international	2012	PMID: 23035815
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.	Novaković S	International journal of oncology	2012	PMID: 22923021
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer.	Kim H	Breast cancer research and treatment	2012	PMID: 22798144
Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes.	Acedo A	Breast cancer research : BCR	2012	PMID: 22632462
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.	Houdayer C	Human mutation	2012	PMID: 22505045
Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing.	Jang JH	Journal of human genetics	2012	PMID: 22217648
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).	Lindor NM	Human mutation	2012	PMID: 21990134
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.	Zhang S	Gynecologic oncology	2011	PMID: 21324516
Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.	Fong PC	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2010	PMID: 20406929
Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation.	Seong MW	Clinical genetics	2009	PMID: 19656164
Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy.	Papi L	Breast cancer research and treatment	2009	PMID: 18821011
Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer.	Sugano K	Cancer science	2008	PMID: 19016756
Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis--a report from the kConFab Investigators.	Spurdle AB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18375895
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.	Easton DF	American journal of human genetics	2007	PMID: 17924331
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.	Risch HA	Journal of the National Cancer Institute	2006	PMID: 17148771
RNA-based analysis of BRCA1 and BRCA2 gene alterations.	Bonatti F	Cancer genetics and cytogenetics	2006	PMID: 17011978
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting.	van der Hout AH	Human mutation	2006	PMID: 16683254
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.	Hamann U	Journal of medical genetics	2002	PMID: 11897832
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.	Meindl A	International journal of cancer	2002	PMID: 11802209
Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families.	Peelen T	British journal of cancer	2000	PMID: 10638982
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f116122-06ef-40a9-934f-9c6654fe75f9	-	-	-	-
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Text-mined citations for rs28897756 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28897756 ...