ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6886A>C (p.Ile2296Leu) (rs576279166)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132216 SCV000187298 likely benign Hereditary cancer-predisposing syndrome 2019-02-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification
Invitae RCV000203848 SCV000261976 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000353391 SCV000383748 uncertain significance Fanconi anemia, complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000410842 SCV000383749 likely benign Breast-ovarian cancer, familial 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl RCV000410842 SCV000488288 uncertain significance Breast-ovarian cancer, familial 2 2016-02-12 criteria provided, single submitter clinical testing
GeneDx RCV001284584 SCV000571484 likely benign not provided 2021-02-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32046981, 30555256, 21811163)
Color Health, Inc RCV000132216 SCV000910979 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000479638 SCV000918806 likely benign not specified 2021-07-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6886A>C (p.Ile2296Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 249818 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.6886A>C has been reported in the literature in an individual affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence of causality (Mehta_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was tested by mini-gene assay and was reported to lead to very slight exon 12 skipping (Meulemans_2020). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six classify as likely benign while three classify as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284584 SCV001470444 likely benign not provided 2019-12-23 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000132216 SCV000787946 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-05 no assertion criteria provided clinical testing

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