ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9685C>T (p.Pro3229Ser) (rs1064793542)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485969 SCV000566379 uncertain significance not provided 2015-04-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9685C>T at the cDNA level, p.Pro3229Ser (P3229S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 9913C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro3229Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro3229Ser occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Pro3229Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000700622 SCV000829385 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 3229 of the BRCA2 protein (p.Pro3229Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 418945). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. 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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