Submissions for variant NM_000059.4(BRCA2):c.631+2T>G (rs81002899)

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031615	SCV001161558	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 = 0.998311
Invitae	RCV000195357	SCV000072910	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-12-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7. 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 as homozygous or compound heterozygous with other pathogenic BRCA2 variants in individuals affected with Fanconi anemia (PMID: 21719596, 15070707, 16825431, 15645491). It has also been observed in individuals affected with breast and/or ovarian cancer (PMID: 11185744, 25682074, 26296701). This variant is also known as IVS7+2T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 9349). This variant falls in intron 7 of the BRCA2 mRNA and is reported to cause skipping of exon 7 (PMID: 11185744, 21719596). The absence of exon 7 in the BRCA2 mRNA results in a translational frameshift and premature stop codon (p.Gly173Serfs*18) that may produce an unstable protein (PMID: 21719596). Functional analysis in mouse stem cells shows that this variant causes a severe phenotype that is unable to rescue cell lethality compared to wild-type BRCA2 (PMID: 21719596). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129071	SCV000183773	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing	Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
GeneDx	RCV000044897	SCV000210249	pathogenic	not provided	2018-10-29	criteria provided, single submitter	clinical testing	This variant, denoted BRCA2 c.631+2 T>G or IVS7+2 T>G, is a splice site mutation which destroys a canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been previously reported as a pathogenic variant in individuals with hereditary breast and/or ovarian cancer with functional data demonstrating that normal mRNA is not produced from the mutated allele (Pyne 2000). and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers.
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031615	SCV000267734	pathogenic	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044897	SCV000296701	pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031615	SCV000327385	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031615	SCV000488785	pathogenic	Breast-ovarian cancer, familial 2	2016-06-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000195357	SCV000591703	pathogenic	Hereditary breast and ovarian cancer syndrome	2016-02-17	criteria provided, single submitter	clinical testing
Color	RCV000129071	SCV000683770	pathogenic	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000195357	SCV000694958	pathogenic	Hereditary breast and ovarian cancer syndrome	2016-07-05	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.631+2T>G variant involves the alteration of a conserved intronic nucleotide located at the invariable splice acceptor site in intron 7 of BRCA2. One in silico tool predicts a damaging outcome for this variant along with 5/5 splice site tools predicting the variant to result in the elimination of the splice donor site in intron 7. These predictions were confirmed by Pyne_J Hum Genet_2000 demonstrating that an RNA splicing product that deletes exon 7 was produced by the chromosome that carries the variant of interest. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. This variant is absent in 121164 control chromosomes while it was reported in several HBOC spectrum patients. Furthermore, multiple clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031615	SCV000778601	pathogenic	Breast-ovarian cancer, familial 2	2019-01-22	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769680	SCV000901093	pathogenic	Breast and/or ovarian cancer	2017-09-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000826135	SCV000967655	pathogenic	Fanconi anemia	2018-02-20	criteria provided, single submitter	clinical testing	The c.631+2T>G variant in BRCA2 has been identified in the homozygous or compoun d heterozygous state in 5 individuals with Fanconi anemia (Myer 2005, Myers 2012 , Wagner 2004), and segregated with disease in 2 individuals from 2 families. It was absent from large population studies. The c.631+2T>G variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown t o cause altered splicing leading to an absent protein (Pyne 2000, Meyer 2005, Bi swas 2011). In summary, this variant meets criteria to be classified as pathogen ic for Fanconi anemia in an autosomal recessive manner. ACMG/AMP criteria applie d: PVS1, PM3_VeryStrong, PS4_Moderate, PM2, PP1.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000195357	SCV000967740	pathogenic	Hereditary breast and ovarian cancer syndrome	2018-02-20	criteria provided, single submitter	clinical testing	The c.631+2T>G variant in BRCA2 has been reported in >15 individuals with BRCA2- associated cancers (Pyne 2000, Wong-Brown 2015, Breast Cancer Information Core ( BIC) database). It was absent from large population studies. The c.631+2T>G vari ant occurs in the invariant region (+/- 1,2) of the splice consensus sequence an d has been shown to cause altered splicing leading to an absent protein (Pyne 20 00, Meyer 2005, Biswas 2011). Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC) . In summary, this variant meets criteria to be classified as pathogenic for her editary breast and ovarian cancer syndrome in an autosomal dominant manner. ACMG /AMP criteria applied: PS4, PM2, PVS1.
OMIM	RCV000009943	SCV000030164	pathogenic	Fanconi anemia, complementation group D1	2007-01-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031615	SCV000054222	pathogenic	Breast-ovarian cancer, familial 2	2013-01-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031615	SCV000147336	pathogenic	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000195357	SCV000587557	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research