ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4610A>G (p.Gln1537Arg) (rs70953659)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766451 SCV000567143 uncertain significance not provided 2015-07-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4610A>G at the cDNA level, p.Gln1537Arg (Q1537R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). Using alternate nomenclature, this variant would be defined as BRCA1 4729A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gln1537Arg 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 Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1537Arg occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Gln1537Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484247 SCV000605887 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing
Invitae RCV000637536 SCV000758999 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1537 of the BRCA1 protein (p.Gln1537Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine 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: 419383). 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 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.
Color RCV000773185 SCV000906750 likely benign Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773185 SCV001184555 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Insufficient evidence

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