Submissions for variant NM_000059.3(BRCA2):c.631+1G>A (rs81002897)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044895	SCV000072908	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-09-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the BRCA2 gene. It is expected to disrupt RNA 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 on the opposite chromosome (in trans) from a pathogenic variant in two individuals affected with Fanconi anemia (FA) (PMID: 16825431, 15004464). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in individuals affected with breast cancer (PMID: 27393621). This sequence change is also known as IVS7+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 9348). Experimental studies have shown that this sequence change results in the out-of-frame skipping of exon 7. This is expected to create a premature translational stop signal (p.Val211Serfs*19), resulting in an absent or disrupted protein product (PMID: 15004464). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131851	SCV000186906	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-30	criteria provided, single submitter	clinical testing	The c.631+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the BRCA2 gene. This mutation, in compound heterozygosity with a nonsense mutation, was previously described in two Fanconi Anemia patients in one family with a family history of early onset breast cancer (Alter BP et al. J. Med. Genet. 2007; 44:1-9). It has also been identified in unselected Chinese and Malaysian breast cancer cohorts (Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103). This alteration (designated as IVS7+1G>A) was demonstrated by RT-PCR to result in aberrant splicing and skipping of exon 7 (coding exon 6) (Popp H et al. Cytogenet. Genome Res. 2003 ;103(1-2):54-7). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113913	SCV000327383	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113913	SCV000677667	likely pathogenic	Breast-ovarian cancer, familial 2	2017-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985563	SCV001133860	pathogenic	not provided	2018-10-15	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Integrated Genetics/Laboratory Corporation of America	RCV000044895	SCV001362777	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-11-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.631+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: five predict the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence that this variant affects mRNA splicing, and demonstrated an out-of-frame skipping of exon 7 in mRNA extracted from patient derived lympoid cell line (Popp_2003). The variant was absent in 250814 control chromosomes (gnomAD). The variant, c.631+1G>A, has been reported in the literature in compound heterozygosity with a premature terminating variant (Y1894X) in individuals who were affected with Fanconi anemia (Wagner_2004, Popp_2003, Alter_2007). The variant was also reported in heterozygosity in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, Bhaskaran_2019). These data indicate that the variant is very likely to be associated with disease. Four 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=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310166	SCV001499760	pathogenic	Breast-ovarian cancer, familial 1	2020-04-02	criteria provided, single submitter	clinical testing
OMIM	RCV000009942	SCV000030163	pathogenic	Fanconi anemia, complementation group D1	2007-01-01	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113913	SCV000147335	pathogenic	Breast-ovarian cancer, familial 2	2003-12-23	no assertion criteria provided	clinical testing