ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: rs80358899
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Total submissions: 19
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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, susceptibility to, 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 ovarian cancer syndrome 2024-02-01 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 2021-08-25 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, susceptibility to, 2 2015-09-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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.
Sema4, Sema4 RCV000163010 SCV002536263 benign Hereditary cancer-predisposing syndrome 2020-10-06 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000045039 SCV002551391 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031646 SCV000054253 benign Breast-ovarian cancer, familial, susceptibility to, 2 2009-10-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031646 SCV000146922 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000045039 SCV001955261 benign not specified no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000031646 SCV004243734 benign Breast-ovarian cancer, familial, susceptibility to, 2 2020-03-02 no assertion criteria provided clinical testing

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