ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3143G>T (p.Gly1048Val) (rs80356899)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112009 SCV001161501 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000314
GeneDx RCV000590820 SCV000210142 uncertain significance not provided 2015-08-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3143G>T at the cDNA level, p.Gly1048Val (G1048V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 3262G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly1048Val 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 Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly1048Val occurs at a position that is not conserved and is located within the DNA-binding domain and the region of interaction with RAD51 and BASC (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Gly1048Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214911 SCV000277268 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-25 criteria provided, single submitter clinical testing The p.G1048V variant (also known as c.3143G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3143. The glycine at codon 1048 is replaced by valine, an amino acid with dissimilar properties. A different alteration located at the same position, p.G1048D, was reported in a cohort of 55630 patients who underwent BRCA1 gene sequencing at a commercial laboratory and was classified as a variant of unknown significance (Judkins T et al. Cancer Res. 2005 Nov 1;65(21):10096-103). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000214911 SCV000683087 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590820 SCV000699006 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112009 SCV000144649 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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