ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3728G>A (p.Gly1243Asp) (rs765545033)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459332 SCV000547266 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1243 of the BRIP1 protein (p.Gly1243Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407810). 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 aspartic acid 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.
GeneDx RCV000519725 SCV000618489 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3728G>A at the cDNA level, p.Gly1243Asp (G1243D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Gly1243Asp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Gly1243Asp occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Gly1243Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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