ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2816C>G (p.Ala939Gly) (rs756490117)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000775412 SCV000909757 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
GeneDx RCV000522943 SCV000616666 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2816C>G at the cDNA level, p.Ala939Gly (A939G) at the protein level,and results in the change of an Alanine to a Glycine (GCA>GGA). This variant has not, to our knowledge, beenpublished in the literature as pathogenic or benign. BRIP1 Ala939Gly was not observed at a significant allele frequencyin large population cohorts (Lek 2016). Since Alanine and Glycine share similar properties, this is considered aconservative amino acid substitution. BRIP1 Ala939Gly occurs at a position that is not conserved and is located in theBRCA1 binding domain (Cantor 2011). In silico analyses predict that this variant is unlikely to alter protein structure orfunction. Based on currently available evidence, it is unclear whether BRIP1 Ala939Gly is a pathogenic or benignvariant. We consider it to be a variant of uncertain significance.
Invitae RCV000553783 SCV000633638 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 939 of the BRIP1 protein (p.Ala939Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs756490117, ExAC 0.003%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 448994). 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 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.

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