ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1012A>G (p.Lys338Glu) (rs397508826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465932 SCV000549401 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 338 of the BRCA1 protein (p.Lys338Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 409360). 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.
Integrated Genetics/Laboratory Corporation of America RCV000586428 SCV000698826 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1012A>G (p.Lys338Glu) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or reputable databases/clinical laboratories. An internal LCA reports the variant to co-occur with a pathogenic BRCA2 variant, c.5073dupA (p.Trp1692fsX3 - classified as pathogenic by LCA). Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

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