ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5975C>T (p.Ser1992Leu) (rs80358830)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044809 SCV000072822 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1992 of the BRCA2 protein (p.Ser1992Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51979). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000236533 SCV000293741 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5975C>T at the cDNA level, p.Ser1992Leu (S1992L) 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 BRCA2 6203C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1992Leu 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 Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1992Leu occurs at a position that is not conserved and is located in the 7th BRC repeat and the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser1992Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572935 SCV000668560 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000572935 SCV000903521 likely benign Hereditary cancer-predisposing syndrome 2017-09-15 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113514 SCV000146743 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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