ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1016A>G (p.Lys339Arg) (rs587781737)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000664302 SCV000788231 likely benign Hereditary breast and ovarian cancer syndrome 2018-04-01 criteria provided, single submitter research The BRCA1 variant designated as c.1016A>G (p.Lys339Arg) is now classified as likely benign. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of 0.20 to 1, which provides moderate evidence that this allele is not associated with similar risk compared to breast other cancer-associated variants in BRCA1. In addition, this variant alters a BRCA1 protein domain where the large majority of missense mutations are benign. This genomic position is not highly conserved. The combined results are consistent with a classification of likely benign. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRCA1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Invitae RCV000664302 SCV000944725 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 339 of the BRCA1 protein (p.Lys339Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. 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: 549761). 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 arginine 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.

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