ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1885C>T (p.Leu629Phe) (rs398122734)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130468 SCV000185334 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000479487 SCV000567342 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1885C>T at the cDNA level, p.Leu629Phe (L629F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 2113C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu629Phe 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 Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu629Phe occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu629Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637481 SCV000758942 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 629 of the BRCA2 protein (p.Leu629Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91762). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The phenylalanine 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 and their clinical significance is uncertain. 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.
Sharing Clinical Reports Project (SCRP) RCV000077670 SCV000109473 uncertain significance Breast-ovarian cancer, familial 2 2011-10-11 no assertion criteria provided clinical testing

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