ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7884A>G (p.Ile2628Met) (rs529779203)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216002 SCV000278485 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000521359 SCV000616659 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7884A>G at the cDNA level, p.Ile2628Met (I2628M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 8112A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2628Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2628Met occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species 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 Ile2628Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000689119 SCV000816757 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2628 of the BRCA2 protein (p.Ile2628Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs529779203, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234006). 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 C0"). 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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