ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1514C>T (p.Ser505Leu) (rs945661395)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457490 SCV000547260 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-03-31 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 505 of the BRIP1 protein (p.Ser505Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRIP1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000569483 SCV000661556 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-16 criteria provided, single submitter clinical testing The p.S505L variant (also known as c.1514C>T), located in coding exon 10 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1514. The serine at codon 505 is replaced by leucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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