ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7232A>C (p.Lys2411Thr) (rs80358950)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
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) RCV000113734 SCV001161531 benign Breast-ovarian cancer, familial 2 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 = 0.00026
Invitae RCV001084424 SCV000073184 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163022 SCV000213510 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000113734 SCV000220593 likely benign Breast-ovarian cancer, familial 2 2014-08-13 criteria provided, single submitter literature only
GeneDx RCV000590755 SCV000279246 likely benign not provided 2020-08-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21990134, 26566278, 21741379, 17924331, 20104584, 20960228, 26689913, 16683254, 24323938, 25085752, 25348012, 23108138, 29036293, 32444794)
Color Health, Inc RCV000163022 SCV000683857 likely benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590755 SCV000695050 likely benign not provided 2017-03-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7232A>C (p.Lys2411Thr) variant involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. This variant was found in 6/121356 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Although, gnomAD, a large, control population that contains ExAC and additional whole genome sequences cites the variant with an allele frequency of 13/246082, predominantly in the other cohort, 9/5480 (1/609), which does exceed the maximal expected allele frequency for a pathogenic variant of 1/1333, therefore, suggesting the variant to be a benign polymorphism. However, this database has yet to be validated by the LCA VSG, therefore, the observation needs to be cautiously considered at this point. The variant of interest was reported in affected individuals via publications, although with limited information (ie, no co-occurrence or co-segregation data). However, a functional study showed the variant of interest acts comparable to wild-type function for Homology-Directed Repair (HDR; Guidugli_2012). BIC reported one individual with a co-occurrence of a pathogenic BRCA1 variant, c.5145delC (p.Tyr1716Ilefs), further supporting the non-pathogenic role of this variant. In addition, multiple reputable clinical laboratories classify the variant as "benign/likely benign". Therefore, taking all lines of available evidence into consideration, the variant of interest has been classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113734 SCV000743329 benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590755 SCV000887906 likely benign not provided 2020-08-13 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646636 SCV001854917 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113734 SCV000147054 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590755 SCV000592103 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Lys2411Thr variant was identified in 2 of 6116 proband chromosomes (frequency: 0.000327) from individuals or families with hereditary breast and ovarian cancer (Borg_2010, Capanu_2011, Laitman_2011) and in 1 of 2796 control chromosomes (freq. 0.00036). The variant was also identified in the following databases: dbSNP (ID: rs80358950) as “With other allele”, ClinVar (as benign by Ambry Genetics and VKGL Data-share Consensus, as likely benign by Counsyl, GeneDx, Quest Diagnostics, Color Genomics, Integrated Genetics, and Invitae, and as uncertain significance by COGR), Clinvitae (4x), LOVD 3.0 (6x), UMD-LSDB (4x as uncertain significance), and ARUP Laboratories (as not pathogenic). The variant was not identified in Cosmic, MutDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 13 of 246082 chromosomes at a frequency of 0.000053 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 9 of 5480 chromosomes (freq: 0.001642), and European (Non-Finnish) in 4 of 111574 chromosomes (freq: 0.000036); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One functional study demonstrated homology-directed repair activity of the variant at a level similar to nonpathogenic variants (Guidugli_2014), and four studies using a multifactorial likelihood-ratio model predict the p.Lys2411Thr variant to be neutral (Easton_2007, Guidugli_2013, Lindor_2012, Pruss_2014_25085752). The p.Lys2411 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000113734 SCV000733295 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001723635 SCV001957465 benign not specified 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.