ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3974G>A (p.Arg1325Lys) (rs921253348)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484697 SCV000567037 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3974G>A at the cDNA level, p.Arg1325Lys (R1325K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4093G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg1325Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Arg1325Lys occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). Based on currently available information, it is unclear whether BRCA1 Arg1325Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509912 SCV000607993 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000808684 SCV000948799 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1325 of the BRCA1 protein (p.Arg1325Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. 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: 419316). 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 lysine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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