ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2263G>A (p.Glu755Lys) (rs41286296)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216413 SCV000273530 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000483305 SCV000564724 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2263G>A at the cDNA level, p.Glu755Lys (E755K) 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 BRCA1 2382G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu755Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu755Lys occurs at a position that is not conserved and is located within the DNA-binding domain as well as a region that binds STAT1 (Ouchi 2000, Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu755Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001057480 SCV001221977 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 755 of the BRCA1 protein (p.Glu755Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with breast cancer (Invitae). However, in those individual a pathogenic allele was also identified in BRCA1, which suggests that this c.2263G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 230102). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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