ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1342C>T (p.Arg448Cys) (rs80358422)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165318 SCV000216040 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-14 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000077254 SCV000145855 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000165318 SCV000911819 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000077254 SCV000488126 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077254 SCV000744408 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077254 SCV000733228 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000043785 SCV000210267 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1342C>T at the cDNA level, p.Arg448Cys (R448C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant, also denoted 1570C>T using alternate nomenclature, has been reported as an unclassified variant in an individual from a family with two or more cases of breast cancer, one of whom was diagnosed before the age of 50 (Meindl 2002). BRCA2 Arg448Cys 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. This variant 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 information, it is unclear whether BRCA2 Arg448Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000203634 SCV000071798 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 448 of the BRCA2 protein (p.Arg448Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80358422, ExAC 0.002%). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 11802209, 30254663). However, a pathogenic BRCA2 variant was also observed in some of these individuals. This variant is also known as 1570C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 51105). 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 cysteine amino acid residue is also 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, 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) RCV000077254 SCV000109051 uncertain significance Breast-ovarian cancer, familial 2 2011-12-19 no assertion criteria provided clinical testing

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