Submissions for variant NM_000059.4(BRCA2):c.1909+1G>A

dbSNP: rs587781629

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129734	SCV000184540	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The c.1909+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the BRCA2 gene. This alteration has been reported in several individuals with a personal history of ovarian cancer (Chong HK et al. PLoS ONE. 2014 May;9:e97408; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Frey MK et al. Gynecol. Oncol. 2015 Nov;139:211-5) as well as in an individual with a history of breast cancer (Shirts BH et al. Genet Med, 2016 10;18:974-81). This alteration has also been reported in a patient with a history of breast and ovarian cancers who also carries the BRCA1 c.-19-?_80+?del alteration (Cardoso FC et al. Hum Genomics, 2018 08;12:39). Additionally, this alteration has been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). RNA assays have shown this alteration to cause the skipping of coding exons 8 and 9 (total exons 9 and 10 in literature), which leads to a transcript that will undergo nonsense-mediated decay (Ambry internal data; Montalban G. et al J Med Genet 2019 02;56(2):63-74.) This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000160183	SCV000210526	likely pathogenic	not provided	2019-07-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); Canonical splice site variant predicted to result in an in-frame deletion of exon 10; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Chong 2014, Frey 2015, Minucci 2015, Shirts 2016, Frey 2017, Cardoso 2018, Marchetti 2018); This variant is associated with the following publications: (PMID: 26296696, 26306726, 24830819, 26845104, 28495237, 30128899, 30103829, 29446198, 31343793)
Invitae	RCV000204822	SCV000260614	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 24830819, 26296696, 26845104, 29446198, 30103829, 31343793). ClinVar contains an entry for this variant (Variation ID: 141283). Studies have shown that disruption of this splice site results in skipping of exons 9-10 and introduces a premature termination codon (PMID: 31343793; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210109	SCV000266038	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160183	SCV000296672	pathogenic	not provided	2020-07-31	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 30103829 (2018), 26845104 (2016), 26296696 (2015)). This variant has also been reported to have a deleterious effect on BRCA2 mRNA splicing (PMID: 31343793 (2019)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238861	SCV000326635	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129734	SCV000688732	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 10 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study reports exon 9-10 skipping in 63.2% of transcripts resulting in a premature stop signal. This variant has been reported in individuals affected with breast or ovarian cancer, (PMID: 26296696, 26681678, 26845104, 28495237, 30103829, 30472649) an individual affected with pancreatic cancer (PMID: 32073954) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002958). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204822	SCV000694584	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1909+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant was absent in 235928 control chromosomes. c.1909+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (example, Chong_2014 and Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000238861	SCV000785268	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129734	SCV002533276	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-22	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492497	SCV002786352	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-04-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474753	SCV004211869	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160183	SCV004564410	pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	The BRCA2 c.1909+1G>A variant (rs587781629) is reported in the literature in individuals with a personal and/or family history of breast or ovarian cancer (Frey 2015, Minucci 2015, Shirts 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 10, which is likely to negatively impact gene function. Consistent with pedictions, functional studies suggest this variant causes skipping of exons 9 and 10, leading to a frameshift (Montalban 2019). Based on available information, this variant is considered to be pathogenic. References: Frey MK et al. Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening. Gynecol Oncol. 2015 Nov;139(2):211-5. PMID: 26296696. Minucci A et al. Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. Expert Rev Mol Diagn. 2015;15(10):1383-403. PMID: 26306726. Montalban G et al. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019 Dec;40(12):2296-2317. PMID: 31343793. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81. PMID: 26845104.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000238861	SCV000591779	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 c.1909+1G>A variant was not identified in the literature, but was identified in the UMD (2X as a causal variant). The c.1909+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a difference in splicing, with an abolishment of the 5' slice donor site in the mutated sequence. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000204822	SCV000916364	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003162573	SCV002758126	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research