ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.520C>T (p.Arg174Cys) (rs41293469)

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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 RCV000132017 SCV000187076 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000132017 SCV000688920 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000217766 SCV000279421 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.520C>T at the cDNA level, p.Arg174Cys (R174C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 748C>T. This variant has been observed in at least two individuals with early-onset familial breast cancer (Thery 2011). RNA and minigene assays have demonstrated that this variant leads to partial exon 7 skipping, producing both full-length and truncated mRNA transcripts in varying proportions (Gaildrat 2012, Di Giacomo 2013). Exon 7 skipping has been reported to create a frameshift ultimately causing a premature nonsense codon, resulting in a truncated protein product that appears to undergo nonsense-mediated mRNA decay (Pyne 2000). BRCA2 Arg174Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg174Cys 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. Although BRCA2 Arg174Cys has been proven to result in incomplete skipping of exon 7, the clinical effect of the alternate splicing mechanism cannot be determined. We therefore consider this to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779978 SCV000916956 uncertain significance not specified 2018-04-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.520C>T (p.Arg174Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Though 5/5 computational tools predict no significant impact on normal splicing, one in silico study predicted potential effects by using 3 ESR-dedicated approaches (Soukarieh 2016). In vitro and in vivo studies indicated that the variant of interest induces partial exon 7 skipping (Thery 2011, Gaildrat 2012, DiGiacomo 2013). Exon 7 skipping is predicted to result in a frameshift, resulting in a truncated protein (that is subject to NMD), however, the in vivo consequence of partial exon 7 skipping is not known. Additionally, when transcribed properly, this variant results in a full length transcript with a missense alteration that could compound the in vivo consequence of this variant. The variant allele was found at a frequency of 4.1e-06 in 246130 control chromosomes. c.520C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Thery 2011, Gaildrat 2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000044608 SCV000072621 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 174 of the BRCA2 protein (p.Arg174Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 individuals from 2 different breast cancer families and although multiple affected individuals are reported for each family, segregation of this variant with disease was not determined (PMID: 21673748, 22962691). ClinVar contains an entry for this variant (Variation ID: 51818). 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 C0"). Multiple studies to determine the impact of exon 7 missense changes on RNA splicing show that this variant results in increased, though incomplete, exon 7 skipping in minigene assays and in patient mRNA (PMID; 22962291, 21673748, 23983145). Exon 7 skipping produces mRNA that codes for an out of frame BRCA2 protein. In summary, this variant is a rare missense change that alters RNA splicing resulting in exon 7 skipping. It is absent from the population and reported in affected individuals/families, however, segregation with disease in these families was not determined. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000083113 SCV000115187 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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