ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6748A>G (p.Thr2250Ala) (rs80358899)

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Total submissions: 17
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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) RCV000031646 SCV000244467 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 = 0.0000203
Invitae RCV000203624 SCV000073052 benign Hereditary breast and ovarian cancer syndrome 2020-11-13 criteria provided, single submitter clinical testing
GeneDx RCV001703440 SCV000210634 likely benign not provided 2019-05-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 24323938, 21990134, 16683254, 20104584, 23683081, 11336395)
Ambry Genetics RCV000163010 SCV000213498 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768603 SCV000324848 likely benign Breast and/or ovarian cancer 2016-02-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045039 SCV000592072 benign not specified 2016-01-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000045039 SCV000593726 likely benign not specified 2016-12-29 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031646 SCV000744499 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163010 SCV000910744 benign Hereditary cancer-predisposing syndrome 2016-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045039 SCV000918947 benign not specified 2021-04-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6748A>G (p.Thr2250Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251358 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00011 vs 0.00075), allowing no conclusion about variant significance. c.6748A>G has been reported in the literature (example, Arver_2001, Blay_2013, Borg_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Multifactorial probability models predict a neutral/benign outcome (example, Lindor_2012, Easton_2007). Multiple co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases as well as at our laboratory (example, BRCA1 c.2035A>T, p.Lys679*; BRCA2 c.771_775delTCAAA, p.Asn257LysfsX17; BRCA2 c.262_263delCT, p.Leu88AlafsX12; BRCA2 c.5351dup, p.Asn1784LysfsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (including the expert panel)/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Research and Development, ARUP Laboratories RCV001642430 SCV001854896 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
Sharing Clinical Reports Project (SCRP) RCV000031646 SCV000054253 benign Breast-ovarian cancer, familial 2 2009-10-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031646 SCV000146922 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 RCV000031646 SCV000733287 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
True Health Diagnostics RCV000163010 SCV000787942 likely benign Hereditary cancer-predisposing syndrome 2017-08-17 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000045039 SCV001906211 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000045039 SCV001955261 benign not specified no assertion criteria provided clinical testing

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