ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3980A>G (p.Gln1327Arg) (rs730881444)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505770 SCV000209894 uncertain significance not provided 2016-12-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3980A>G at the cDNA level, p.Gln1327Arg (Q1327R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA1 4099A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gln1327Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Gln1327Arg 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). 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 Gln1327Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509776 SCV000607835 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000637725 SCV000759198 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1327 of the BRCA1 protein (p.Gln1327Arg). 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: 182079). 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.
Counsyl RCV000662402 SCV000784821 uncertain significance Breast-ovarian cancer, familial 1 2017-01-05 criteria provided, single submitter clinical testing
Color RCV000509776 SCV000909283 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing

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