ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5962G>A (p.Val1988Ile) (rs28897739)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477598 SCV000549862 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1988 of the BRCA2 protein (p.Val1988Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs28897739, ExAC 0.06%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91430). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000567451 SCV000661255 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000477598 SCV000886452 likely benign Hereditary breast and ovarian cancer syndrome 2018-05-29 criteria provided, single submitter research The BRCA2 variant designated as NM_000059.3: c.5962G>A (p.Val1988Ile) is classified as likely benign. This variant is listed in population databases and is found in 1 out of 1250 individuals with Finnish ancestry. Computer software programs predict that this variant is likely to be benign. This variant is found in exon 11, in a domain where non-truncating mutations are usually benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yielding a likelihood ratio of pathogenicity of 0.14 to 1 (Thompson, et al., 2003, PMID:2900794) providing evidence that this allele is less likely to cause cancer. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRCA2 function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Fulgent Genetics,Fulgent Genetics RCV000763891 SCV000894826 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
Sharing Clinical Reports Project (SCRP) RCV000076947 SCV000108744 uncertain significance Breast-ovarian cancer, familial 2 2011-01-06 no assertion criteria provided clinical testing

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