ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044895 SCV000072908 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-22 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Research and Development, ARUP Laboratories RCV001642219 SCV001854332 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
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

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