Total submissions: 8
| 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 | Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation |
| Consortium of Investigators of Modifiers of BRCA1/2 |
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. |
| OMIM | RCV000009942 | SCV000030163 | pathogenic | Fanconi anemia, complementation group D1 | 2007-01-01 | no assertion criteria provided | literature only | |
| Breast Cancer Information Core |
RCV000113913 | SCV000147335 | pathogenic | Breast-ovarian cancer, familial 2 | 2003-12-23 | no assertion criteria provided | clinical testing |