ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2T>G (p.Met1Arg) (rs80358547)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131870 SCV000186925 pathogenic Hereditary cancer-predisposing syndrome 2014-07-22 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),Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113010 SCV000145997 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000131870 SCV000683520 pathogenic Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113010 SCV000326799 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044102 SCV000916857 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a damaging effect of the variant on protein function. RT-PCR analysis showed the variant to result in no aberrant splicing (Santos_2014). However, the since this variant abolishes the normal initiation codon, the closest ATG is in exon 4, indicating an out-of-frame protein lacking important domains for transactivation and phosphorylation (Santos_2014). The variant allele was found at a frequency of 8.1e-06 in 246154 control chromosomes. c.2T>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Azzollini_2016, Fernandes_2016, Labidi-Galy_2017), however in one family the variant was absent in one affected individual, indicating a lack of segregation (Santos_2014). Overall, these data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000044102 SCV000072115 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-24 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 present in population databases (rs80358547, ExAC <0.01%). This variant has been reported in individuals from families with hereditary breast and/or ovarian cancer, although the variant did not segregate completely with disease in one of the families studied (PMID: 24607278, 24916970). In addition, different changes at the initiator codon (c.1A>G, c.2T>A, c.2T>C, c.3G>A) have also been observed in individuals with breast and/or ovarian cancer (PMID: 25330149, 14647210, 21769658, 18182601, 24156927, Invitae). ClinVar contains an entry for this variant (Variation ID: 51385). 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.
Mendelics RCV000044102 SCV000838716 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759594 SCV000889013 pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing

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