ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3050C>T (p.Pro1017Leu) (rs747907706)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165849 SCV000216598 likely benign Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000231204 SCV000291030 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1017 of the BRIP1 protein (p.Pro1017Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs747907706, ExAC <0.01%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354), and in individuals with breast cancer and unaffected controls (PMID: 26921362). CilnVar contains an entry for this variant (Variation ID: 186283). 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.
GeneDx RCV000586787 SCV000567106 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3050C>T at the cDNA level, p.Pro1017Leu (P1017L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was identified in 3/13,213 cases and 2/5,242 controls in a breast cancer case-control study, as well as in at least one individual with ovarian cancer (Ramus 2015, Easton 2016). BRIP1 Pro1017Leu was not observed at a significant frequency in large population cohorts (Lek 2016). BRIP1 Pro1017Leu is located in the BRCA1 binding domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRIP1 Pro1017Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586787 SCV000699711 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3050C>T (p.Pro1017Leu) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. It is not located in currently known functional domains. This variant was found in 2/121372 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). It has been reported in one patient with ovarian cancer however without strong evidence for or against pathogenicity (Ramus_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000662372 SCV000784765 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-09 criteria provided, single submitter clinical testing
Color RCV000165849 SCV000911428 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing

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