ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3666G>C (p.Glu1222Asp) (rs1555587312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548913 SCV000635910 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1222 of the BRCA1 protein (p.Glu1222Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. 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 aspartic 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000567011 SCV000665897 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-20 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755852 SCV000883458 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing The BRCA1 c.3666G>C;p.Glu1222Asp variant has not been described in the medical literature, in gene-specific databases, or in the ClinVar database. The variant is not listed in the dbSNP variant database or in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic BRCA1 variants are causative for hereditary breast and ovarian cancer (OMIM#113705).

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