ClinVar Miner

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

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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 RCV000129600 SCV000184384 likely benign Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
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.
Invitae RCV000168454 SCV000219151 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-31 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 individuals affected with breast and/or ovarian cancer (PMID: 27257965, 30702160). 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160016 SCV000602799 uncertain significance not specified 2018-09-11 criteria provided, single submitter clinical testing The BRCA2 c.352C>T; p.Arg118Cys variant (rs375125172), is reported in the literature in at least one individual affected with breast cancer (Zhong 2016). This variant is reported with conflicting classifications in ClinVar (Variation ID: 91803), and is found in the African population with an overall allele frequency of 0.03% (4/15,298 alleles) in the Genome Aggregation Database. The arginine at codon 118 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg118Cys variant is uncertain at this time. References: Zhong X et al. Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients. PLoS One. 2016 Jun 3;11(6):e0156789.
Integrated Genetics/Laboratory Corporation of America RCV000160016 SCV000694701 uncertain significance not specified 2019-09-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.352C>T (p.Arg118Cys) 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. 4/4 computational tools via ALAMUT predict no significant impact on normal splicing although a disruption of an ESE splice site is predicted. In a minigene assay system, this variant was reported to produce 74% of the canonical transcript and low levels of delta 4, delta 4,5 and delta 4,5,6 transcripts (Fraile-Bethencourt_2019). However, the in-vivo impact of these findings have yet to be corroborated by functional studies. The variant allele was found at a frequency of 4e-05 in 251000 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.352C>T has been reported in the literature in individuals affected with Breast Cancer (Zhang_2016, Bhaskaran_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000129600 SCV000911378 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590557 SCV001133762 uncertain significance not provided 2019-07-24 criteria provided, single submitter clinical testing
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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