ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4211C>T (p.Ser1404Leu) (rs41293489)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160075 SCV000210332 uncertain significance not provided 2014-06-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4211C>T at the cDNA level, p.Ser1404Leu (S1404L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1404Leu 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 Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1404Leu occurs at a position that is moderately conserved across species and is located in the region of interaction with POLH. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ser1404Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637430 SCV000758888 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1404 of the BRCA2 protein (p.Ser1404Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs41293489, ExAC 0.003%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182208). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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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