ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4099G>A (p.Glu1367Lys) (rs786202998)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235899 SCV000292715 uncertain significance not provided 2015-12-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4099G>A at the cDNA level, p.Glu1367Lys (E1367K) 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 4218G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1367Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1367Lys occurs at a position that is not conserved and is located in the SCD domain and in a region known to interact with multiple proteins (Narod 2004, Paul 2014). While protein based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, splicing based in silico analyses predict this variant to result in the gain of a cryptic splice donor site, possibly altering normal gene splicing. In the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 Glu1367Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780986 SCV000918712 uncertain significance not specified 2018-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4099G>A (p.Glu1367Lys) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 242170 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; 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 is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics RCV001021855 SCV001183523 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Insufficient evidence

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