ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2944A>C (p.Ile982Leu) (rs28897717)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167800 SCV000072103 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 982 of the BRCA2 protein (p.Ile982Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs28897717, ExAC 0.008%). This variant has been reported in a family with breast or ovarian cancer (PMID: 16905680). It has also been reported in an individual in the Breast Cancer Information Core (BIC) database (PMID: 10923033). However, in that individual, a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.2944A>C substitution in BRCA2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 51375). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Ambry Genetics RCV000131312 SCV000186285 benign Hereditary cancer-predisposing syndrome 2014-05-27 criteria provided, single submitter clinical testing
GeneDx RCV000044090 SCV000210296 likely benign not specified 2018-02-15 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587861 SCV000225161 uncertain significance not provided 2015-04-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044090 SCV000591837 uncertain significance not specified 2014-01-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044090 SCV000600535 uncertain significance not specified 2017-06-14 criteria provided, single submitter clinical testing
Color RCV000131312 SCV000683513 likely benign Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587861 SCV000694651 likely benign not provided 2017-08-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2944A>C (p.Ile982Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 5/120330 control chromosomes at a frequency of 0.0000416, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature in an affected individual, without strong evidence for causality. Three clinical diagnostic laboratories classified this variant as uncertain significance, and one other lab classified it as benign, all without evidence for independent evaluaiton. UMD and BIC databases cite this variant in three individuals as co-occurring with pathogenic variants BRCA1 c.4327C>T (p.Arg1443X), BRCA1 c.4964_4982del (p.Ser956=fs), and BRCA2 c.7638-7647del (p.Lys257X), respectively, supporting the non-pathogenic role of this variant. Taken together, this variant is classified as likely benign.
GeneKor MSA RCV000131312 SCV000821931 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113118 SCV000146144 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000587861 SCV000778657 uncertain significance not provided 2017-05-08 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131312 SCV000787925 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing

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