ClinVar Miner

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

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Total submissions: 12
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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 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163022 SCV000213510 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Counsyl RCV000113734 SCV000220593 likely benign Breast-ovarian cancer, familial 2 2014-08-13 criteria provided, single submitter literature only
GeneDx RCV000223307 SCV000279246 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000223307 SCV000592103 uncertain significance not specified 2013-11-08 criteria provided, single submitter clinical testing
Color RCV000163022 SCV000683857 likely benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2019-06-27 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113734 SCV000147054 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000113734 SCV000733295 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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