ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1838T>G (p.Leu613Arg) (rs587780646)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129425 SCV000184195 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129425 SCV000903069 likely benign Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Counsyl RCV000238635 SCV000489192 uncertain significance Breast-ovarian cancer, familial 2 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000221850 SCV000278839 likely benign not specified 2017-07-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000590456 SCV000694575 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1838T>G (p.Leu613Arg) variant involves the alteration of a non-conserved nucleotide and is located outside of some of the known domains/repeats in BRCA2 protein (InterPro). 3/5 in silico tools predict damaging outcome for this variant. This variant was found in 2/117904 control chromosomes (including ExAC) at a frequency of 0.0017%, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.07503%). However, in a gnomAD database, its allele frequency in Latino population is 0.052% (17/32544 chromosomes) which is only slightly lesser than or in similar range to the maximal expected allele frequency. Whether this variant is a benign/rare polymorphism specific to Latino population needs to be further investigated. This variant has been reported in one Latino (Mexican) patient with breast cancer who had positive family history of breast (a sister and a paternal cousin) and other cancers (leukemia and prostate cancer) (Ruiz-Flores_2002). It has also been reported three times in a database (UMD) without co-occurrence with other deleterious variants in BRCA1/2 genes. Classification of this variant by clinical laboratories (via ClinVar) is conflicting: while two laboratories have classified it as likely benign, other four laboratories as uncertain significance. Taken together, this variant is currently classified as a Variant of Unknown Significance.
Invitae RCV000122900 SCV000166158 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 613 of the BRCA2 protein (p.Leu613Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs587780646, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer and in an unaffected individual (PMID: 12442275). This variant is also known as c. 2066T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 135791). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221850 SCV000296608 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238635 SCV000297506 likely benign Breast-ovarian cancer, familial 2 2013-09-11 no assertion criteria provided clinical testing

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