ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.352C>T (p.Arg118Cys) (rs375125172)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160016 SCV000602799 uncertain significance not specified 2016-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129600 SCV000184384 likely benign Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000129600 SCV000911378 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000590557 SCV000210234 uncertain significance not provided 2018-02-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.352C>T at the cDNA level, p.Arg118Cys (R118C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA2 580C>T. This variant has been observed in at least one individual with breast cancer (Zhong 2016). BRCA2 Arg118Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). 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 evidence, it is unclear whether BRCA2 Arg118Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590557 SCV000694701 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.352C>T (p.Arg118Cys) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/117946 control chromosomes at a frequency of 0.0000593, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In literature, this variant has been reported in two breast and/or ovarian cancer patients (one as germline another as somatic) without strong evidence for pathogenicity (Beltrame_2015, Zhong_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000168454 SCV000219151 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 118 of the BRCA2 protein (p.Arg118Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs375125172, ExAC 0.04%). This variant has been reported in an individual affected with breast cancer (PMID: 27257965). ClinVar contains an entry for this variant (Variation ID: 91803). 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 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 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240706 SCV000265924 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Sharing Clinical Reports Project (SCRP) RCV000077711 SCV000109514 uncertain significance Breast-ovarian cancer, familial 2 2006-12-06 no assertion criteria provided clinical testing

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