ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3G>A (p.Met1Ile) (rs80358650)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044328 SCV000072341 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-02 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the BRCA2 mRNA. An alternate in-frame methionine downstream of the initiator codon is located at codon 124, which could potentially rescue translational initiation. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 21203900, 21769658, 20104584). In addition, different changes at the initiator codon (c.1A>G, c.2T>A, c.2T>C, c.2T>G) have also been observed in individuals with breast and/or ovarian cancer (PMID: 24916970, 24607278, 25330149, 24156927, 14647210, and Invitae database). This variant is also known as 231G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 51579). Based on a multifactorial likelihood algorithm using family history, co-occurrence and co-segregation data, this variant has been determined to have a high probability of being pathogenic (PMID: 21769658). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the N-terminal part of the BRCA2 protein that interacts with PALB2 (residues 18-40), which is critical for BRCA2-mediated homologous recombinational DNA repair (PMID: 16793542, 22678057, 19369211). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162893 SCV000213380 pathogenic Hereditary cancer-predisposing syndrome 2017-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000083102 SCV000296498 pathogenic Breast-ovarian cancer, familial 2 2016-06-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083102 SCV000326954 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000083102 SCV000605705 pathogenic Breast-ovarian cancer, familial 2 2017-01-20 criteria provided, single submitter clinical testing
Counsyl RCV000083102 SCV000786194 pathogenic Breast-ovarian cancer, familial 2 2018-03-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083102 SCV000115176 pathogenic Breast-ovarian cancer, familial 2 2009-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083102 SCV000145999 not provided Breast-ovarian cancer, familial 2 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044328 SCV000587525 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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