ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9613_9614delinsCT (p.Ala3205Leu) (rs276174926)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080951 SCV000073880 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129271 SCV000184031 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000766658 SCV000210801 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing BRCA2 c.9613_9614delGCinsCT has been observed in several individuals with a history of early onset breast cancer and in at least one individual with prostate cancer (Malone 2000, Maier 2014, El Saghir 2015). However, several functional studies have concluded that this variant did not show any remarkable splicing consequences (Caux-Moncoutier 2009, Sanz 2010). In addition, BRCA2 c.9613_9614delGCinsCT was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA2 c.9613_9614delGCinsCT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. This variant occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 c.9613_9614delGCinsCT 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 RCV000120371 SCV000592297 uncertain significance not specified 2013-07-31 criteria provided, single submitter clinical testing
Color RCV000129271 SCV000684078 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120371 SCV000916855 uncertain significance not specified 2018-05-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9613_9614delinsCT (p.Ala3205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246148 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (2.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.9613_9614delinsCT has been reported in the literature in affected individuals. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two internal samples also carried different pathogenic variants (CDH1 c.382delC/p.His128Ilefs and BRCA1 c.2475delC/p.Asp825fsX21) suggesting a non-pathogenic role for the variant of interest. At least one publication reports experimental evidence and suggests no impact on splicing in patient lymphocytes (Sanz_2010). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766658 SCV001133987 uncertain significance not provided 2019-07-24 criteria provided, single submitter clinical testing
ITMI RCV000120371 SCV000084523 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000114136 SCV000147677 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735632 SCV000863770 uncertain significance Breast and/or ovarian cancer 2013-05-03 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.