ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5512G>A (p.Val1838Met) (rs730881501)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160014 SCV000210230 uncertain significance not provided 2014-02-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5512G>A at the cDNA level, p.Val1838Met (V1838M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val1838Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. BRCA1 Val1838Met occurs at a position that is well conserved across species and is located in the BRCT2 domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Val1838Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000689723 SCV000817388 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-15 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1838 of the BRCA1 protein (p.Val1838Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182173). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Val1838Glu) has been determined to be likely pathogenic (PMID: 21990134, 18375895, 27272900, 20516115). This suggests that the valine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.