ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3541G>A (p.Val1181Ile) (rs56336919)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112112 SCV001161585 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000066
Invitae RCV000590151 SCV000076239 likely benign not provided 2019-02-27 criteria provided, single submitter clinical testing
GeneDx RCV000590151 SCV000210148 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3541G>A at the cDNA level, p.Val1181Ile (V1181I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant, also known as 3660G>A using alternate nomenclature, was observed in at least one individual with a family history of breast and/or ovarian cancer (Konecny 2011). BRCA1 Val1181Ile was observed at an allele frequency of 0.05% (14/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Val1181Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000203659 SCV000494376 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509845 SCV000607801 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000590151 SCV000699040 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3541G>A (p.Val1181Ile) variant involves the alteration of a non-conserved nucleotide, located outside of any functional domain, and results in a replacement of a Valine (V) with an Isoleucine (I). Both residues are medium size and hydrophobic, therefore this Valine to Isoleucine substitution most likely not to alter the physico-chemical properties of the protein. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11/121136 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.000424 (7/16506). These frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), however, considering the high frequency in South Asian subpopulation and the homozygote occurrence; it is possible this variant is a rare polymorphism found primarily in populations of South Asian. This variant has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. This variant has been predicted to be neutral by studies based on sequence alignment, chemical difference measurement, and conservation analysis ( Abkevich et al._2004, Pavlicek et al._2004). Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.
Color RCV000509845 SCV000911018 likely benign Hereditary cancer-predisposing syndrome 2016-05-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590151 SCV001133556 likely benign not provided 2019-04-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112112 SCV000144784 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 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.