ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122900 SCV000166158 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129425 SCV000184195 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing The p.L613R variant (also known as c.1838T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1838. The leucine at codon 613 is replaced by arginine, an amino acid with dissimilar properties. This variant was observed in 1 of 50 Mexican breast cancer patients, but also in 1 of 65 Mexican control individuals (Ruiz-Flores P et al. Hum. Mutat. 2002 Dec;20(6):474-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985248 SCV000296608 uncertain significance not provided 2020-03-20 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000221850 SCV000694575 uncertain significance not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1838T>G (p.Leu613Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 241822 control chromosomes, predominantly at a frequency of 0.00051 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.1838T>G has been reported in the literature 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) and in a cohort of patients with MSI-high colorectal cancer (Deihimi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 (likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000129425 SCV000903069 likely benign Hereditary cancer-predisposing syndrome 2017-01-03 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358539 SCV001554301 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Leu613Arg variant was identified in 1 of 64 proband chromosomes (frequency: 0.02) from individuals or families with breast cancer and was present in 1 of 130 control chromosomes (frequency: 0.008) from healthy individuals (Ruiz-Flores 2002). The variant was also identified in dbSNP (ID: rs587780646) as "With other allele" and ClinVar (classified as likely benign by SCRP and GeneDx; and as uncertain significance by Invitae, Ambry Genetics and three other submitters). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was identified in control databases in 17 of 236466 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 17 of 32544 chromosomes (freq: 0.0005), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu613 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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