ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9296A>G (p.Asn3099Ser) (rs730881571)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160168 SCV000210503 uncertain significance not provided 2014-07-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9296A>G at the cDNA level, p.Asn3099Ser (N3099S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn3099Ser 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 Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn3099Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Asn3099Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000794362 SCV000933767 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 3099 of the BRCA2 protein (p.Asn3099Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182262). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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