ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4253T>C (p.Leu1418Ser) (rs397509157)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237031 SCV000294105 uncertain significance not provided 2016-03-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4253T>C at the cDNA level, p.Leu1418Ser (L1418S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). Using alternate nomenclature, this variant would be defined as BRCA1 4372T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1418Ser 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 Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Leu1418Ser occurs at a position that is conserved across species and is located in the SCD domain, the Coiled-coil Region, and a region known to interact with multiple proteins (Narod 2004, Sy 2009, Paul 2014). 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 Leu1418Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509656 SCV000608212 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000781025 SCV000918785 uncertain significance not specified 2018-10-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4253T>C (p.Leu1418Ser) 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 was absent in 246204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4253T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.