ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.428C>G (p.Pro143Arg) (rs587782795)

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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 RCV000132345 SCV000187434 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000132345 SCV000688865 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-16 criteria provided, single submitter clinical testing
GeneDx RCV000590737 SCV000210238 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.428C>G at the cDNA level, p.Pro143Arg (P143R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 656C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro143Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Pro143Arg is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Pro143Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590737 SCV000694764 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.428C>G (p.Pro143Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant does not lay within a known functional domain (InterPro) or repeat, although 5/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control datasets of ExAC and gnomAD at a frequency of 0.0000248 and 0.00003615 (3/120990 and 10/ 276612 chrs tested, respectively), exclusively in Latino cohorts (at a similar frequencies ~0.0002910). Although, the observed frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), the variant may represent a rare, ethnic-specific polymorphism. To our knowledge, the variant of interest has not been reported in affected individuals via publications, but is cited as VUS by multiple clinical diagnostic laboratories/reputable databases. Considering all, the variant is classified as VUS until additional information becomes available.
Invitae RCV000637494 SCV000758955 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 143 of the BRCA2 protein (p.Pro143Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs587782795, ExAC 0.03%). This variant has been observed in an individual with breast cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA1, which suggests that this c.428C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142885). 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 disruptive, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160019 SCV000296633 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing

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