ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4771G>A (p.Gly1591Ser) (rs587782825)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132402 SCV000187494 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000203874 SCV000260007 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1591 of the BRCA1 protein (p.Gly1591Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs587782825, ExAC 0.001%). This variant has been observed in individuals affected with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 142926). 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 serine 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.
GeneDx RCV000588705 SCV000321435 uncertain significance not provided 2016-06-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4771G>A at the cDNA level, p.Gly1591Ser (G1591S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant, defined as BRCA1 4890G>A using alternate nomenclature, was observed in one case of contralateral breast cancer (Borg 2010). BRCA1 Gly1591Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1591Ser occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Gly1591Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588705 SCV000699174 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing Variant summary: The c.4771G>A (p.Gly1591Ser) in BRCA1 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.000008 (1/121362 chrs tested). The variant is also reported in control population of gnomAD at a frequency of 0.00001 (3/282554 chrs tested), exclusively in individuals of European descent. However, since the resource is still in early beta mode, the occurrences were not captured in pbGP. The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.001. The variant has been reported in affected individuals without strong evidence of causality. In addition, the variant is cited as VUS by several reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Color RCV000132402 SCV000909011 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing

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