ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2963C>T (p.Ser988Leu) (rs397507206)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656788 SCV000209948 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2963C>T at the cDNA level, p.Ser988Leu (S988L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). Using alternate nomenclature, this variant would be defined as BRCA1 3082C>T. This variant has been observed in at least one breast and ovarian cancer family (Lu 2012). BRCA1 Ser988Leu was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the RAD51 binding region (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser988Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656788 SCV000225000 uncertain significance not provided 2015-03-18 criteria provided, single submitter clinical testing
Invitae RCV000544423 SCV000635874 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-09 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 988 of the BRCA1 protein (p.Ser988Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs397507206, ExAC 0.003%) but has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37494). 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 leucine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000776172 SCV000911271 likely benign Hereditary cancer-predisposing syndrome 2018-03-12 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031075 SCV000053671 benign Breast-ovarian cancer, familial 1 2012-02-01 no assertion criteria provided clinical testing

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