ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2994G>C (p.Lys998Asn) (rs757225144)

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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 RCV000220971 SCV000273265 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000217097 SCV000278905 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2994G>C at the cDNA level, p.Lys998Asn (K998N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Lys998Asn 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Lys998Asn occurs at a position that is not conserved and is located within the region responsible for interacting with BRCA1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Lys998Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000544259 SCV000633646 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 998 of the BRIP1 protein (p.Lys998Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs757225144, ExAC 0.001%). This variant has not been reported in the literature in individuals with 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 asparagine 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 and their clinical significance is uncertain. 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.
Mendelics RCV000989984 SCV001140746 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Color RCV000220971 SCV001339563 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing

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