ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6772G>A (p.Glu2258Lys) (rs730881549)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572828 SCV000661305 likely benign Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
GeneDx RCV000585930 SCV000210404 uncertain significance not provided 2015-12-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6772G>A at the cDNA level, p.Glu2258Lys (E2258K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 7000G>A. While this variant was identified as a de novo finding in a child with an autism spectrum disorder, it has not, to our knowledge, been reported in an individual noted to have a personal or family history of cancer (Neale 2012). BRCA2 Glu2258Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2258Lys 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 information, it is unclear whether BRCA2 Glu2258Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585930 SCV000694996 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6772G>A (p.Glu2258Lys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. Glu2258 is not conserved across species and is not located in a known functional domain. This variant was found in 1/120952 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was identified as a de novo occurrence in one patients with ASD, but it is unknown if this family had a history of cancer. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information is available.
Invitae RCV000809521 SCV000949674 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2258 of the BRCA2 protein (p.Glu2258Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs730881549, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182233). 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 lysine 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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