ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.475G>A (p.Val159Met) (rs80358702)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218417 SCV000275357 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Functionally-validated splicing mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113649 SCV000146940 pathogenic Breast-ovarian cancer, familial 2 2005-09-27 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113649 SCV000327083 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000236273 SCV000293311 likely pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.475G>A at the cDNA level. Located in the last nucleotide of exon 5, it is predicted to disrupt the natural splice donor site. RNA analysis has demonstrated that this variant causes abnormal splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Machackova 2008). This variant, also reported as BRCA2 703G>A using alternate nomenclature, has been identified in several individuals with breast and/or ovarian cancer (Machackova 2008, Kim 2012, Pritzlaff 2017, Park 2017). Although the nucleotide substitution results in the change of a Valine to a Methionine at codon 159, 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.475G>A was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 475, is conserved through mammals. Based on the current evidence, we consider this variant to be likely pathogenic.

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