ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4552C>A (p.Gln1518Lys) (rs80356881)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223155 SCV000276234 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing Rarity in general population databases (dbSNP, ESP, 1000 Genomes);Insufficient or Conflicting Evidence;in silico models in agreement (benign)
Invitae RCV000227811 SCV000289804 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 1518 of the BRCA1 protein (p.Gln1518Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482259 SCV000566816 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4552C>A at the cDNA level, p.Gln1518Lys (Q1518K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4671C>A. This variant has been identified in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Sibille-Hoang 1998). BRCA1 Gln1518Lys was not observed in large population cohorts (Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1518Lys occurs at a position that is not conserved and is located in the SCD domain and in a region known to interact with multiple other proteins (Narod 2004, Clark 2012, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Gln1518Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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