ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3416G>T (p.Ser1139Ile) (rs80357228)

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Total submissions: 10
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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) RCV000112090 SCV001161584 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 = 0.000012
Invitae RCV000048184 SCV000076197 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132045 SCV000187105 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing ​<span style="background-color:initial">The p.S1139I <span style="background-color:initial">variant (also known as c.3416G>T), located in coding exon 9 of the BRCA1 <span style="background-color:initial">gene, results from a G to T substitution at nucleotide position 3416. The serine at codon 1139 is replaced by isoleucine, an amino acid with dissimilar properties. In one study, this variant was detected in 1/705 women with contralateral breast cancer and 0/1398 women with unilateral breast cancer (Borg A et al. Hum. Mutat. <span style="background-color:initial">2010 Mar;31:E1200-40). This alteration was also detected with a BRCA2<span style="background-color:initial"> VUS, p.T431I, in 1/251 German high risk breast/ovarian cancer patients (Meyer P et al. Hum. Mutat<span style="background-color:initial">. 2003 Sep;22:259). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.<span style="background-color:initial"> Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 likely benign not provided 2020-03-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20104584, 12938098, 23704879, 31131967, 16267036, 10923033)
Color Health, Inc RCV000132045 SCV000902967 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194406 SCV001363931 uncertain significance not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3416G>T (p.Ser1139Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3416G>T has been reported in the literature in individuals affected with breast/ovarian cancer (Borg_2010, Meyer_2003). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant four times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Research and Development, ARUP Laboratories RCV001662083 SCV001878305 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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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