ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.425G>T (p.Ser142Ile) (rs397507713)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213168 SCV000275905 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000521547 SCV000617461 likely pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.425G>T at the cDNA level. Located in the last nucleotide of exon 4, it disrupts a natural splice donor site and causes abnormal splicing. This variant was reported in a patient with a personal and family history of breast cancer, and RNA analyses of lymphocytes from this patient demonstrated that BRCA2 c.425G>T causes skipping of exon 4 (Brandão 2011). Although the nucleotide substitution results in the change of a Serine to an Isoleucine at codon 142 (Ser142Ile), we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA2 c.425G>T was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 425, is conserved through mammals. Based on the currently available evidence, we consider this variant to be likely pathogenic.
Mendelics RCV000709287 SCV000838731 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000521547 SCV000887807 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing
Color RCV000213168 SCV000911390 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000709287 SCV000916899 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.425G>T affects the last nucleotide position in exon 4. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Three predict the variant weakens a 5' donor site. The variant was absent in 274472 control chromosomes. c.425G>T has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Brandao 2011). The authors of this study also reported experimental evidence evaluating the variant's impact, and demonstrated that the variant c.425G>T gives rise to exon 4 skipping, causing a frameshift (predicted to result in a PTC; described at the protein level as p.Gly106ValdelfsX9), however they didn't find evidence for NMD. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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