rs28897756

chr13-32379913-G-Achr13-32379913-G-Cchr13-32379913-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):c.9117G>A(p.Pro3039=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000372 in 1,613,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P3039P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:36
• Conservation: PhyloP100: 4.22

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32379913-G-A is Pathogenic according to our data. Variant chr13-32379913-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38215.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379913-G-A is described in Lovd as [Pathogenic]. Variant chr13-32379913-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9117G>A	p.Pro3039=	splice_region_variant, synonymous_variant	23/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9117G>A	p.Pro3039=	splice_region_variant, synonymous_variant	23/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248378 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460930 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000249 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 31, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 09, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Nov 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	Apr 23, 2024	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). -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	Observed in multiple breast/ovarian cancer families (Peelan 2000, Risch 2006, Novakovic 2012, Tea 2014, de Juan 2015, Gabald Barrios 2017, Sun 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Published functional studies demonstrate a damaging effect: disruption of a splice donor site which causes aberrant RNA processing, specifically skipping of exon 23, and predicted to result in protein truncation (Peelen 2000, Bonatti 2006, Acedo 2012, Colombo 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 9345G>A; This variant is associated with the following publications: (PMID: 22798144, 17011978, 22505045, 22632462, 26026974, 25948282, 28477318, 29084914, 31447099, 32398771, 32658311, 17924331, 23451180, 23035815, 22923021, 17148771, 20507642, 22217648, 18375895, 10638982, 9133456, 21324516, 18821011, 25556971, 28008555, 24156927, 27000661, 21702907, 28740454, 28873162, 27271530, 25186627, 28724667, 25382762, 29805665, 29907814, 29339979, 28825054, 30702160, 31957001, 31143373, 29176636, 21990134, 31825140, 32853339, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 06, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 03, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 01, 2021	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

Medulloblastoma;C0040588:Tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 28, 2023

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 09, 2021

Diagnosis: Breast cancer Pathology: Invasive ductal breast carcinoma IHC: ER:+, PR:+, HER2:- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28897756; hg19: chr13-32954050; COSMIC: COSV99061599; COSMIC: COSV99061599;