ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2135T>C (p.Leu712Pro) (rs80358490)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131476 SCV000186463 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113019 SCV000146010 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000131476 SCV000906889 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing
Counsyl RCV000113019 SCV000786270 uncertain significance Breast-ovarian cancer, familial 2 2018-04-02 criteria provided, single submitter clinical testing
GeneDx RCV000590581 SCV000210282 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2135T>C at the cDNA level, p.Leu712Pro (L712P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu712Pro in large population cohorts (Lek 2016). BRCA2 Leu712Pro is located not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether BRCA2 Leu712Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590581 SCV000694592 uncertain significance not provided 2016-07-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2135T>C (p.Leu712Pro) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a benign outcome. This variant is outside of known functional domains in BRCA2 protein. This variant is absent in approximately 120854 control chromosomes from ExAC. This variant has been reported in at least one clinical sample in a study (Mattocks_2010), without strong evidence for or against pathogenicity. It has also been reported in one sample by BIC without co-occurrence with another deleterious variant in BRCA1/2. But in one of two samples reported in UMD, this variant co-occured with another deleterious variant BRCA2 p.Tyr1894X. Although the possibility that this patient had Faconi Anemia can not be ruled out, it is more likely that the variant of interest is not pathogenic. Multiple clinical diagnostic laboratories and a reputable database (UMD) have classified this variant as uncertain significance. Taken all lines of evidence together, this variant is classified as VUS-possibly benign.
Invitae RCV000043949 SCV000071962 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 712 of the BRCA2 protein (p.Leu712Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033), the Universal Mutation Database (PMID: 22144684) and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 51248). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590581 SCV000889003 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing

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