ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4083G>A (p.Met1361Ile) (rs374192364)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129891 SCV000184708 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000766669 SCV000570599 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4083G>A at the cDNA level, p.Met1361Ile (M1361I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). Using alternate nomenclature, this variant would be defined as BRCA1 4202G>A. This variant has been observed in at least one individual with ovarian cancer (Alsop 2012). BRCA1 Met1361Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met1361Ile occurs at a position that is not conserved and is located within the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Met1361Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000478992 SCV000591485 uncertain significance not specified 2012-04-06 criteria provided, single submitter clinical testing
Invitae RCV000637459 SCV000758919 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1361 of the BRCA1 protein (p.Met1361Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs374192364, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37564). 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 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.
Sharing Clinical Reports Project (SCRP) RCV000031145 SCV000053745 uncertain significance Breast-ovarian cancer, familial 1 2011-03-16 no assertion criteria provided clinical testing

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.