ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6215C>G (p.Ser2072Cys) (rs80358862)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044872 SCV000072885 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2072 of the BRCA2 protein (p.Ser2072Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs80358862, ExAC 0.003%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12373604, 25136594, 21120943). However, in two affected individuals different pathogenic alleles have been identified in the BRCA1 gene, which suggests that this c.6215C>G variant was not the primary cause of disease (PMID: 10923033, Invitae). This variant is also known as 6443C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 38027). 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 C15"). 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.
Ambry Genetics RCV000130542 SCV000185411 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000766634 SCV000210385 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6215C>G at the cDNA level, p.Ser2072Cys (S2072C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant, also known as 6443C>G using alternate nomenclature, has been observed in at least three individuals with a personal or family history of breast and/or ovarian cancer (Jakubowska 2002, Caux-Moncoutier 2010, Ruiz 2014). BRCA2 Ser2072Cys was also identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA2 Ser2072Cys was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the BRC8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). 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 Ser2072Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130542 SCV000683759 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-10 criteria provided, single submitter clinical testing
Counsyl RCV000031608 SCV000785358 uncertain significance Breast-ovarian cancer, familial 2 2017-07-12 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769699 SCV000901115 uncertain significance Breast and/or ovarian cancer 2016-06-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031608 SCV000054215 uncertain significance Breast-ovarian cancer, familial 2 2007-06-14 no assertion criteria provided clinical testing
ITMI RCV000120333 SCV000084485 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031608 SCV000146794 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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