ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2312T>C (p.Leu771Ser) (rs730881481)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159967 SCV000210126 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2312T>C at the cDNA level, p.Leu771Ser (L771S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). This variant, also known as BRCA1 c.2431T>C by alternate nomenclature, has been reported in at least one individual with serous ovarian cancer (Li 2013). BRCA1 Leu771Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Leu771Ser occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu771Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000163092 SCV000213597 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238847 SCV000296360 uncertain significance Breast-ovarian cancer, familial 1 2016-04-05 criteria provided, single submitter clinical testing
Color RCV000163092 SCV000683026 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing
Invitae RCV001061346 SCV001226084 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 771 of the BRCA1 protein (p.Leu771Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary breast and/or ovarian cancer (PMID: 29088781, 24321281, 30702160). ClinVar contains an entry for this variant (Variation ID: 182145). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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