ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3416G>T (p.Ser1139Ile) (rs80357228)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048184 SCV000076197 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 1139 of the BRCA1 protein (p.Ser1139Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 20104584, 12938098). ClinVar contains an entry for this variant (Variation ID: 54873). 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 isoleucine 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.
Ambry Genetics RCV000132045 SCV000187105 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Michigan Medical Genetics Laboratories,University of Michigan RCV000112090 SCV000195919 uncertain significance Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000235128 SCV000210146 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3416G>T at the cDNA level, p.Ser1139Ile (S1139I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). This variant, previously reported as BRCA1 3535G>T using alternate nomenclature, has been reported in at least two women with breast cancer (Meyer 2003, Borg 2010). BRCA1 Ser1139Ile 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 Serine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1139Ile occurs at a position that is not conserved and is not located in a known functional domain. 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 Ser1139Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132045 SCV000902967 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112090 SCV000144756 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000048184 SCV000586892 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-14 no assertion criteria provided clinical testing

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