ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4357A>G (p.Lys1453Glu) (rs397507330)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166887 SCV000217703 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166887 SCV000906082 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing
GeneDx RCV000589133 SCV000278851 uncertain significance not provided 2016-10-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4357A>G at the cDNA level, p.Lys1453Glu (K1453E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 4585A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1453Glu 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 Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys1453Glu occurs at a position that is not conserved and is located in the BRC3 domain and the RAD51 and POLH binding regions (Cole 2011, Roy 2012, Buisson 2014). 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 Lys1453Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000589133 SCV000840195 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000589133 SCV000694766 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4357A>G variant affects a non-conserved nucleotide, resulting in an amino acid change from Lys to Glu. 4/5 in-silico tools predict this variant to be benign. This variant was found in 1/119132 control chromosomes at a frequency of 0.0000084, which does not exceed maximal expected frequency of a pathogenic BRCA2 allele (0.0007503). In addition, several clinical laboratories classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000204586 SCV000260762 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1453 of the BRCA2 protein (p.Lys1453Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs397507330, 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: 37897). 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 glutamic acid 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589133 SCV000887814 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000119103 SCV000054083 uncertain significance Breast-ovarian cancer, familial 2 2006-12-11 no assertion criteria provided clinical testing

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