ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4061C>T (p.Thr1354Met) (rs80358656)

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Total submissions: 22
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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) RCV000077319 SCV000244445 benign Breast-ovarian cancer, familial 2 2015-08-10 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 = 0.0000803
Invitae RCV001085458 SCV000072352 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000077319 SCV000154102 likely benign Breast-ovarian cancer, familial 2 2014-04-12 criteria provided, single submitter literature only
CSER _CC_NCGL, University of Washington RCV000148432 SCV000190131 likely benign Breast neoplasm 2014-06-01 criteria provided, single submitter research
GeneDx RCV001353774 SCV000210601 likely benign not provided 2021-03-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 12845657, 21520273, 21156238, 21990134, 24055113, 25637381, 24323938, 24728327, 26306726, 11336395, 20104584, 16847550, 20960228, 26689913, 24504028, 27153395, 28202063)
Ambry Genetics RCV000163005 SCV000213493 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120326 SCV000334467 likely benign not specified 2015-09-08 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120326 SCV000593744 likely benign not specified 2016-04-15 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000163005 SCV000679715 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163005 SCV000683597 likely benign Hereditary cancer-predisposing syndrome 2015-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120326 SCV000694739 benign not specified 2019-12-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4061C>T (p.Thr1354Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 243646 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00014 vs 0.00075), allowing no conclusion about variant significance. The variant, c.4061C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Arver_2001 , Capalbo_2006 , deSanjose_2003 , Laitman_2011) without strong evidence for causality. Cosegregation studies in a family with a history of breast cancer found that this variant did not segregate with disease (Jalkh_2017). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.2071_2071delA, p.Arg691Aspfs (BIC database), CDH1 c.3G>A, p.Met1Ile (Jalkh_2017)], providing supporting evidence for a benign role. Ten other submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as benign (n=3) or likely benign (n=7). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077319 SCV000743293 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077319 SCV000744449 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000120326 SCV000864300 likely benign not specified 2017-12-29 criteria provided, single submitter clinical testing BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Mendelics RCV000077319 SCV001139080 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286109 SCV001472635 likely benign none provided 2019-10-24 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646237 SCV001854787 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
ITMI RCV000120326 SCV000084478 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077319 SCV000109116 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077319 SCV000146367 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 RCV001353774 SCV000591886 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Thr1354Met variant was identified in 6 of 5256 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast or ovarian cancer (Giannini 2006, Borg 2010, de Sanjosé 2003, Yang 2011). The variant was also identified in the following databases: dbSNP (ID: rs80358656) as ” With other allele”, ClinVar (17 x as benign by ENIGMA, VKGL data share, Invitae, Ambry Genetics, SCRP, as likely benign by EGL Genetics, COGR, Color Genomics, Integrated Genetics, Counsyl, GeneDx and as uncertain significance by BIC), COGR (as likely benign/benign), Cosmic (1x confirmed somatic ovarian carcinoma), LOVD 3.0 (7x as benign or predicted neutral), UMD-LSDB (17 x as likely neutral), BIC Database (12 x as uncertain significance), ARUP Laboratories (as “class 1,not pathogenic or of no clinical significance”). The variant was not identified in MutDB or Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 3 individuals with hereditary breast or ovarian cancer and 3 different co-occurring pathogenic variants were identified in each of these individuals (BRCA2, c.7007G>C, p.Arg2336Pro), (BRCA1, c.4096+1G>A, r.spl?) and (BRCA2, c.1103C>A, p.Ser368*), increasing the likelihood that the p.Thr1354Met variant does not have clinical significance. The variant was identified in control databases in 34 of 269620 chromosomes at a frequency of 0.00013 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23878 chromosomes (freq: 0.00004), Other in 2 of 6330 chromosomes (freq: 0.0003), Latino in 4 of 32684 chromosomes (freq: 0.0001), European Non-Finnish in 22 of 124492 chromosomes (freq: 0.00018), Ashkenazi Jewish in 4 of 9770 chromosomes (freq: 0.0004), and South Asian in 1 of 28178 chromosomes (freq: 0.000035); the variant was not observed in the East Asian or European Finnish populations. The p.Thr1354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein (Capanu 2011, Easton 2007, Lindor 2012); 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.
Human Genetics - Radboudumc,Radboudumc RCV000120326 SCV001952259 benign not specified no assertion criteria provided clinical testing

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