ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.293A>G (p.Asn98Ser) (rs781121675)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567628 SCV000661464 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000567628 SCV000903185 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000478530 SCV000566291 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.293A>G at the cDNA level, p.Asn98Ser (N98S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was not observed among 13,213 breast cancer cases, but was identified in 1/5,242 unaffected controls (Easton 2016). BRIP1 Asn98Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Asn98Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206440 SCV000259646 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 98 of the BRIP1 protein (p.Asn98Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs781121675, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 219651). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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