ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3262C>T (p.Pro1088Ser) (rs80358572)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086347 SCV000072172 benign Hereditary breast and ovarian cancer syndrome 2020-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129258 SCV000184018 likely benign Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000585942 SCV000210587 likely benign not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27376475, 28651617, 26517685, 23525077, 20858050, 30151275)
Counsyl RCV000031410 SCV000488689 uncertain significance Breast-ovarian cancer, familial 2 2016-05-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044159 SCV000694684 benign not specified 2021-03-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3262C>T (p.Pro1088Ser) 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 4.3e-05 in 233286 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.3262C>T has been reported in the literature as a reportedly somatic occurrence in non-MSI positive samples from patients with esophageal adenocarcinoma (example, Dulac_2013) and in the MSI instable FFPE specimen derived from a patient with hereditary endometrial carcinoma in whom a germline pathogenic variant in the MSH6 gene had been identified (Jori_2015, patient 5, MSI unstable, MSH6 variant c.3729_3732dupATTA). The variant has also been reported as a germline mutation in the literature in patients with breast/ovarian cancer and head and neck squamous cell carcinoma (HNSCC), without strong evidence for causality (example, Coulet_2010, Buzolin_2017, Schenkel_2016, Chandrasekharappa_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the BIC database (2 - BRCA1 exon13ins6kb, 1 - BRCA1 c.3549_3550delinsT (p.K1183fsX), and 1 - BRCA1 c.4357+1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=8, VUS, n=2). Taken together, based on at-least 5 reports of the occurrence of this variant in patients with an alternative molecular basis of disease attributed to mutations in MSH6 (n=1) or BRCA1 (n=4) genes and the majority concordance among peers supporting a neutral outcome as outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031410 SCV000743282 likely benign Breast-ovarian cancer, familial 2 2015-06-15 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031410 SCV000744436 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000585942 SCV000805688 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129258 SCV000902754 benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585942 SCV001470413 likely benign not provided 2020-03-18 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642304 SCV001854757 uncertain significance 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) RCV000031410 SCV000054015 benign Breast-ovarian cancer, familial 2 2008-10-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031410 SCV000146198 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000585942 SCV000778661 likely benign not provided 2017-07-27 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000585942 SCV001743080 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000585942 SCV001905951 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000585942 SCV001960092 likely benign not provided no assertion criteria provided clinical testing

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