ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4070T>G (p.Leu1357Arg) (rs55796504)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130026 SCV000184852 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx RCV000160072 SCV000210328 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4070T>G at the cDNA level, p.Leu1357Arg (L1357R) at the protein level, and results in the change of a Leucine to an Arginine (CTA>CGA). Using alternate nomenclature, this variant would be defined as BRCA2 4298T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1357Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu1357Arg occurs at a position that is not conserved and is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, it is unclear whether BRCA2 Leu1357Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000409740 SCV000488012 uncertain significance Breast-ovarian cancer, familial 2 2015-12-16 criteria provided, single submitter clinical testing
Invitae RCV000462928 SCV000549580 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1357 of the BRCA2 protein (p.Leu1357Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141478). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color RCV000130026 SCV000683599 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781066 SCV000918870 uncertain significance not specified 2018-03-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4070T>G (p.Leu1357Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 242424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4070T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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