ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4987G>C (p.Val1663Leu) (rs587781763)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129985 SCV000184809 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000167888 SCV000218534 likely benign Hereditary breast and ovarian cancer syndrome 2017-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000766617 SCV000564784 uncertain significance not provided 2015-01-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4987G>C at the cDNA level, p.Val1663Leu (V1663L) at the protein level, and results in the change of a Valine to a Leucine (GTC>CTC). Using alternate nomenclature, this variant would be defined as BRCA2 5215G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val1663Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val1663Leu occurs at a position that is highly variable across species and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Val1663Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483840 SCV000600619 uncertain significance not specified 2017-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000483840 SCV000916902 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4987G>C (p.Val1663Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was absent in 118590 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4987G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported in published literature. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications "uncertain significance" or "likely benign." This includes one submission that cites the variant to co-occur with a pathogenic BRCA2 variant (exact variant not provided) in trans in a pt not indicated to have Faconi Anemia. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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