ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2325T>G (p.Asn775Lys) (rs375146450)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206272 SCV000259485 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 775 of the BRIP1 protein (p.Asn775Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs375146450, ExAC 0.003%) but has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 219556). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000520323 SCV000618232 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2325T>G at the cDNA level, p.Asn775Lys (N775K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Asn775Lys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Asn775Lys occurs at a position that is conserved across species and is located in the helicase domain V (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Asn775Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571248 SCV000666184 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571248 SCV000689330 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000571248 SCV000821959 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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