ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1927A>G (p.Ser643Gly) (rs80357105)

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Total submissions: 7
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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) RCV000077502 SCV001161504 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 = 0.00055
GeneDx RCV000236055 SCV000293185 uncertain significance not provided 2015-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1927A>G at the cDNA level, p.Ser643Gly (S643G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant has been previously published as BRCA1 2046A>G, having been observed in a breast cancer family (Stoppa-Lyonnet 1997). BRCA1 Ser643Gly 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 Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser643Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the DNA binding domain (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser643Gly is pathogenic or benign.
Counsyl RCV000077502 SCV000785055 uncertain significance Breast-ovarian cancer, familial 1 2017-03-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775173 SCV000909358 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing
Invitae RCV001296354 SCV001485315 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 643 of the BRCA1 protein (p.Ser643Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 29371908, 18273839, 9150149, 19471317). This variant is also known as 2046A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 54402). 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.
Sharing Clinical Reports Project (SCRP) RCV000077502 SCV000109302 uncertain significance Breast-ovarian cancer, familial 1 2009-02-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077502 SCV000144251 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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