Submissions for variant NM_000059.4(BRCA2):c.8488-1G>A

dbSNP: rs397507404

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031747	SCV001161647	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.992712
GeneDx	RCV000160152	SCV000210474	likely pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Canonical splice site variant producing both in-frame and out-of-frame transcripts (Howlett et al., 2002; Acedo et al., 2012; Santos et al., 2014; Acedo et al., 2015); Published functional studies are inconclusive: marginal sensitivity to PARP inhibitor and other DNA damaging agents and wild type levels of RAD51 foci formation (Stoepker et al., 2015); Reported in the homozygous state in an individual with Fanconi anemia that was described as mild, whose lympohoblasts exhibited modest MMC sensitivity; as well as a second individual with non-obstructive azoospermia (Howlett et al., 2002; Kasak et al., 2022); Observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Acedo et al., 2012; Kim et al., 2012; Santos et al., 2014; Peixoto et al., 2015; Fernandes et al., 2016; Shin et al., 2016; Park et al., 2018; Cotrim et al., 2019; Ryu et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8716-1G>A; This variant is associated with the following publications: (PMID: 24916970, 24301060, 28726806, 29446198, 26247049, 29907814, 22632462, 24607278, 27383479, 26834852, 25382762, 24259538, 28332257, 16115142, 25447315, 27741520, 15645491, 22798144, 19464302, 29673794, 25525159, 29625052, 26580448, 30606148, 30350268, 30078507, 28111427, 29790872, 31131967, 33008098, 31447099, 33397043, 31589614, 28888541, 25583207, 32986223, 34235180, 34413315, 35535697, 32719484, 34645131, 35264596, 36988593, 36451132, 12065746)
Ambry Genetics	RCV000213906	SCV000278235	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	The c.8488-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 19 of the BRCA2 gene. This mutation was previously reported in a homozygous state in one Fanconi anemia patient of subtype D1 with a family history of consanguinity (Howlett NG et al. Science. 2002 Jul;26:297(5581):606-9). Results from various functional splicing assays performed on this alteration demonstrated that this mutation results in three to five different abnormally spliced transcripts, which includes production of an abnormal transcript that loses 12 nucleotides of exon 20, a transcript that retains intron 19, and another transcript with exon 20 skipping (Acedo et al. Breast Cancer Res. 2012 May; 25:14(3):R87; Santos C et al. J. Mol. Diagn. 2014 May;16(3):324-34; Acedo et al Hum. Mutat. 2015 Feb;36(2):210-21; Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Invitae	RCV000231355	SCV000283345	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 19 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer, autosomal recessive Fanconi anemia (PMID: 22632462, 24301060, 24607278, 27741520, 31331294). This variant is also known as Ex19-1G>A, IVS19-1G>A. ClinVar contains an entry for this variant (Variation ID: 38164). 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: 12065746). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products ( PMID: 22632462, 24607278, 25382762; Invitae). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031747	SCV000327907	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031747	SCV000584075	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-11	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160152	SCV000600809	pathogenic	not provided	2021-11-10	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing (PMIDs: 22632462 (2012), 24607278 (2014)). In the published literature, the variant has been reported in individuals with Fanconi anemia (PMID: 12065746 (2002)) and with breast/ovarian cancer (PMIDs: 24607278 (2014), 30078507 (2018), 30606148 (2019)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000031747	SCV000677712	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-03-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213906	SCV000683971	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical -1 position of intron 19 splice acceptor site of the BRCA2 gene. This variant is also known as IVS19-1G>A in the literature. RNA studies have shown that this variant results in several different abnormally spliced transcripts, including a transcript missing 12 nucleotides of exon 20, a transcript that retains intron 19, and another transcript with exon 20 skipping (PMID: 12065746, 22632462, 24607278, 25382762; ClinVar SCV000278235.5). Functional studies have shown that the mutant protein results in a decreased number of cells with RAD51 foci and reduced focus size, confers a moderate defect in homologous recombination, and disrupts replication fork protection function (PMID: 32354836). This variant has been observed in over ten individuals affected with breast and/or ovarian cancer (PMID: 22632462, 22798144, 24916970, 27741520, 33008098; Chheda 2020, DOI: 10.4103/CRST.CRST_1; Color data) and in an individual affected with colorectal cancer with family history of breast cancer (PMID: 33309985). This variant has also been reported in a homozygous individual affected with a mild form of Fanconi anemia (PMID: 12065746), and cells derived from this individual showed a modest sensitivity to a DNA damaging agent, suggesting that this variant may be hypomorphic in some individuals. 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.
Mendelics	RCV000231355	SCV000838877	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763329	SCV000894006	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	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000231355	SCV000916934	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8488-1G>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: Two predict that the variant abolishes a 3' acceptor site. Several publications report experimental evidence that this variant affects mRNA splicing (e.g. Acedo_2012, Santos_2014). The variant was absent in 251414 control chromosomes. c.8488-1G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Acedo_2012, Kim_2012, Peixoto_2014, Fernandes_2016) and Fanconi anemia (e.g. Howlett_2002). These data indicate that the variant is likely to be associated with disease.Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant impairs protein function (e.g. Howlett_2002, Godthelp_2006). 13 other 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000031747	SCV001139218	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000231355	SCV001653113	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-06	criteria provided, single submitter	clinical testing	The c.8488-1G>A variant in BRCA2 has been reported in the heterozygous state in at least 8 individuals with BRCA2-related cancers, and in the homozygous state in 1 individual with Fanconi anemia (Acedo 2012 PMID: 22632462, Santos 2014 PMID: 24607278, Park 2017 PMID: 28111427, Li 2018 PMID: 30078507 , Palmero 2018 PMID: 29907814, Cotrim 2019 PMID: 30606148). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 38164) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Sequencing of patient RNA confirms that this variant leads to abnormal splicing (Howlett 2002 PMID: 12065746, Acedo 2012 PMID: 22632462, Santos 2014 PMID: 24607278). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate.
Revvity Omics, Revvity	RCV000160152	SCV002019186	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing
DASA	RCV002221480	SCV002498791	pathogenic	BRCA2-Related Disorders	2022-04-10	criteria provided, single submitter	clinical testing	The c.8488-1G>A variant is located in a canonical splice-site, and it is predicted to alter gene function due to either exon skipping or nonsense-mediate decay – NMD, and the variant is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 38164; PMID: 22632462; PMID: 24607278; PMID: 27741520; PMID: 25382762; PMID: 22632462) - PS4. This variant is not present in population databases (rs397507404- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031747	SCV002512285	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-08-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderate, PM2 moderate
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000031747	SCV002538628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-01	criteria provided, single submitter	research
Baylor Genetics	RCV000031747	SCV004183430	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473221	SCV004211837	pathogenic	Familial cancer of breast	2023-10-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160152	SCV004226687	likely pathogenic	not provided	2022-08-05	criteria provided, single submitter	clinical testing	PP3, PP5, PM2, PS3_moderate, PVS1_moderate
OMIM	RCV000009920	SCV000030141	pathogenic	Fanconi anemia complementation group D1	2002-07-26	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031747	SCV000054354	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-09-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000231355	SCV000587958	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Gharavi Laboratory, Columbia University	RCV000160152	SCV000809442	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003162283	SCV002758379	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research