ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1376T>C (p.Leu459Ser) (rs587781799)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130063 SCV000184890 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000483293 SCV000567764 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1376T>C at the cDNA level, p.Leu459Ser (L459S) 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/ has been previously published as BRCA2 1604T>C. This variant was observed in a woman with lung cancer and a family history of breast, ovarian, prostate and pancreatic cancer; however, she was also found to carry a pathogenic variant in EGFR (Yu 2014). BRCA2 Leu459Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu459Ser is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Leu459Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000231284 SCV000283168 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 459 of the BRCA2 protein (p.Leu459Ser). The leucine residue is weakly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (rs587781799, ExAC no frequency). This variant has been reported in an individual affected with lung cancer and with a family history of breast and ovarian cancers (PMID: 24736080). However, in that individual and in a relative with lung cancer, a likely pathogenic allele was also identified in EGFR, which suggests that this c.1376T>C variant was not the primary cause of lung cancer. ClinVar contains an entry for this variant (Variation ID: 141505). 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 serine 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 or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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