ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9898C>T (p.Pro3300Ser) (rs770868371)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235254 SCV000293490 uncertain significance not provided 2015-11-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9898C>T at the cDNA level, p.Pro3300Ser (P3300S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). Using alternate nomenclature, this variant would be defined as BRCA2 10126C>T. This variant was observed in at least one individual with esophageal squamous cell carcinoma (Hu 2002). BRCA2 Pro3300Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro3300Ser occurs at a position that is conserved across species and is not located in a known functional domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro3300Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637357 SCV000758812 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 3300 of the BRCA2 protein (p.Pro3300Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs770868371, ExAC 0.01%). This variant has been reported in individuals affected with esophageal and breast cancer (PMID: 11948123, 28664449). This variant is also known as c.10126C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 246104). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770738 SCV000902221 uncertain significance Breast and/or ovarian cancer 2017-06-15 criteria provided, single submitter clinical testing

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