Submissions for variant NM_000059.4(BRCA2):c.8488-1G>A (rs397507404)

Total submissions: 17

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 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	2018-05-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8488-1G>A or IVS19-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 19 of the BRCA2 gene. Splicing assays have demonstrated that this variant, also reported as BRCA2 8716-1G>A using alternate nomenclature, results in skipping of exon 20 (Acedo 2012, Santos 2014, Acedo 2015). This disruption would be predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, these studies have detected several additional in-frame and out-of-frame transcripts (Howlett 2002, Acedo 2012, Santos 2014, Acedo 2015). Functional studies performed by Stoepker et. al. (2015) demonstrated that this variant showed only marginal sensitivity to PARP inhibitor and other DNA damaging agents and wild type levels of RAD51 foci formation. This variant has been observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Acedo 2012, Kim 2012, Santos 2014, Peixoto 2015, Fernandes 2016, Shin 2016, Park 2018), but has also been observed in an unaffected control patient (Naslavsky 2017). This variant was reported in the homozygous state in an individual with Fanconi anemia; however, the phenotype of this patient was classified as mild (Howlett 2002). Based on the currently available evidence, we consider BRCA2 c.8488-1G>A to be a likely pathogenic variant.
Ambry Genetics	RCV000213906	SCV000278235	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-11	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	likely pathogenic	Hereditary breast and ovarian cancer syndrome	2019-11-16	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 mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast cancer (PMID: 22632462, 24607278, 27741520) and Fanconi anemia (PMID: 24301060). This variant is also known as Ex19-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38164). Experimental studies have shown that this variant alters RNA splicing, but the clinical significance of these findings is uncertain (PMID: 22632462, 24607278, 25382762). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031747	SCV000327907	pathogenic	Breast-ovarian cancer, familial 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 2	2016-02-11	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160152	SCV000600809	pathogenic	not provided	2017-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000031747	SCV000677712	pathogenic	Breast-ovarian cancer, familial 2	2015-03-09	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000213906	SCV000683971	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-12-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000231355	SCV000838877	pathogenic	Hereditary breast and 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 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000231355	SCV000916934	pathogenic	Hereditary breast and 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 2	2019-05-28	criteria provided, single submitter	clinical testing
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 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 and 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