ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5189A>G (p.Asn1730Ser) (rs80357171)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132266 SCV000187349 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235134 SCV000210205 uncertain significance not specified 2016-08-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5189A>G at the cDNA level, p.Asn1730Ser (N1730S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 5308A>G. Lee et al. (2010) concluded that BRCA1 Asn1730Ser behaved similar to wild type on in vitro assays interrogating transcription, stability, and binding. BRCA1 Asn1730Ser 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 Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asn1730Ser occurs at a position that is not conserved and is located within the BRCT 1 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). 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 Asn1730Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000077607 SCV000488026 uncertain significance Breast-ovarian cancer, familial 1 2015-12-28 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000235134 SCV000588062 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985247 SCV000605907 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing
Color RCV000132266 SCV000905816 benign Hereditary cancer-predisposing syndrome 2015-11-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235134 SCV000916820 uncertain significance not specified 2018-11-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5189A>G (p.Asn1730Ser) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276920 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5189A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Pavlicek_2004, Chen_2006). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was shown to have no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity (Lee_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified as VUS, one classified as benign . Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077607 SCV000109410 uncertain significance Breast-ovarian cancer, familial 1 2010-11-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077607 SCV000145375 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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