ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2186T>C (p.Ile729Thr) (rs431825296)

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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 RCV000166578 SCV000217380 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing The p.I729T variant (also known as c.2186T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2186. The isoleucine at codon 729 is replaced by threonine, an amino acid with similar properties. In a large case-control study using multi-ethnic Asian cohorts, this variant was detected in 1/1213 breast cancer patients and 4/1423 healthy controls (Lai KN et al. BMC Cancer, 2017 02;17:149). This alteration was also identified in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS ONE, 2016 Jun;11:e0156789). This amino acid position is not well 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240800 SCV000265949 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Invitae RCV000637814 SCV000759293 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 729 of the BRCA2 protein (p.Ile729Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs431825296, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 28222693, 27257965). ClinVar contains an entry for this variant (Variation ID: 96780). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine 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.
3DMed Clinical Laboratory Inc RCV000677830 SCV000803990 uncertain significance Ovarian cancer 2017-04-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758870 SCV000887768 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763882 SCV000894817 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112184 SCV001269823 uncertain significance Fanconi anemia, complementation group D1 2018-01-12 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 RCV000082901 SCV001269824 likely benign Breast-ovarian cancer, familial 2 2018-01-12 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.
Color RCV000166578 SCV001339332 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082901 SCV000114975 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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