ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6833T>G (p.Ile2278Ser) (rs1555284865)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522420 SCV000618090 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6833T>G at the cDNA level, p.Ile2278Ser (I2278S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC). Using alternate nomenclature, this variant would be defined as BRCA2 7061T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2278Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile2278Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ile2278Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000819360 SCV000960015 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 2278 of the BRCA2 protein (p.Ile2278Ser). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine 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: 449728). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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