ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4254A>G (p.Ile1418Met) (rs1064793378)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485031 SCV000565961 uncertain significance not provided 2015-03-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4254A>G at the cDNA level, p.Ile1418Met (I1418M) 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 4482A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1418Met 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 Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1418Met occurs at a position that is not conserved across species and is located in the region required for interaction with POLH and stimulation of POLH DNA dimerization activity (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ile1418Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000804771 SCV000944696 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1418 of the BRCA2 protein (p.Ile1418Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. 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: 418703). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine 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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