ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.380G>A (p.Ser127Asn) (rs80357189)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048339 SCV000076352 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 127 of the BRCA1 protein (p.Ser127Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer; however, the variant was absent in the breast tumor, suggesting this is a neutral change (PMID: 18824701). ClinVar contains an entry for this variant (Variation ID: 55012). Experimental studies have shown that this missense change results in a protein with E3 ligase activity similar to that of wild type BRCA1 (PMID: 25823446). 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.
Ambry Genetics RCV000131802 SCV000186854 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000478246 SCV000564714 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.380G>A at the cDNA level, p.Ser127Asn (S127N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant, also known as BRCA1 499G>A using alternate nomenclature, has been observed in the germline of at least one individual with early-onset breast cancer (Spearman 2008). BRCA1 Ser127Asn was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser127Asn occurs at a position that is conserved across species and is located in the BRD7 binding domain (Harte 2010). 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 Ser127Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131802 SCV000688454 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing
Counsyl RCV000112413 SCV000785724 uncertain significance Breast-ovarian cancer, familial 1 2017-11-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112413 SCV000145199 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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