ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3417G>T (p.Lys1139Asn) (rs145625991)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235818 SCV000293339 uncertain significance not provided 2015-10-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3417G>T at the cDNA level, p.Lys1139Asn (K1139N) at the protein level, and results in the change of a Lysine to a Asparagine (AAG>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 c.3645G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys1139Asn occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010, Uniprot). 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 Lys1139Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000823718 SCV000964588 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1139 of the BRCA2 protein (p.Lys1139Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 246043). 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 asparagine 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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