ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1723G>A (p.Glu575Lys) (rs397508902)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167785 SCV000075582 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 575 of the BRCA1 protein (p.Glu575Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs397508902, ExAC 0.006%). This variant has been reported in one of two sisters affected with breast cancer (PMID: 14647443), and in unrelated individuals with breast cancer (PMID: 20858050, 14973102). ClinVar contains an entry for this variant (Variation ID: 54334). Experimental studies in cell lines derived from an affected individual have shown that this missense change may affect BRCA1 function. However, the observed reduction in double strand break repair fidelity could be due to another variant present in the cell line (PMID: 14647443). 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.
GeneDx RCV000656786 SCV000210110 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1723G>A at the cDNA level, p.Glu575Lys (E575K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also denoted BRCA1 1842G>A using alternate nomenclature, has been observed in at least two individuals with breast cancer, as well as in an individual from a breast/ovarian cancer family (Coupier 2004, Suter 2004, Anczukow 2008). Although Coupier et al. (2004) demonstrated that BRCA1 Glu575Lys was associated with impaired DNA break repair activity, the variant did not co-segregate with breast cancer in the family they presented. Of note, this variant is referred to as Q575K in this paper, which is presumably the result of a typographical error; however the c. nomenclature matches with the current variant. BRCA1 Glu575Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu575Lys occurs at a position that is not conserved and is located within the DNA binding domain and a region known to interact with RAD50 and STAT1 (Zhong 1999, Ouchi 2000, Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Glu575Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000166298 SCV000217082 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047569 SCV000600264 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing
Counsyl RCV000662632 SCV000785316 uncertain significance Breast-ovarian cancer, familial 1 2017-07-05 criteria provided, single submitter clinical testing

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