ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6922A>G (p.Lys2308Glu) (rs398122570)

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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 RCV000130466 SCV000185331 uncertain significance Hereditary cancer-predisposing syndrome 2013-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000216979 SCV000279853 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6922A>G at the cDNA level, p.Lys2308Glu (K2308E) 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 7150A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2308Glu 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 Lys2308Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain. 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 Lys2308Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779927 SCV000916859 uncertain significance not specified 2018-05-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6922A>G (p.Lys2308Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276360 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6922A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000076980 SCV000108777 likely benign Breast-ovarian cancer, familial 2 2011-08-26 no assertion criteria provided clinical testing

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