ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9209C>T (p.Ser3070Phe) (rs747837583)

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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 RCV000166326 SCV000217112 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000166326 SCV000689181 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-06 criteria provided, single submitter clinical testing
GeneDx RCV000220690 SCV000278887 uncertain significance not provided 2017-05-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9209C>T at the cDNA level, p.Ser3070Phe (S3070F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 9437C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser3070Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser3070Phe occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser3070Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000554071 SCV000635724 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 3070 of the BRCA2 protein (p.Ser3070Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 186691). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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