ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.79A>G (p.Ile27Val) (rs80359034)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164869 SCV000215554 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113106 SCV000146131 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000164869 SCV000903894 benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
GeneDx RCV000499803 SCV000618196 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.79A>G at the cDNA level, p.Ile27Val (I27V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 307A>G. BRCA2 Ile27Val was observed in four relatives from one family: one individual with pancreatic cancer, one with malignant melanoma, and two with no personal history of cancer (Bartsch 2010). In a series of functional assays by Xia et al. (2006), this variant was similar to wild type in homologous recombination and double-strand break repair (HR/DSBR) activity, inhibition of HR/DSBR activity with over-expression, PALB2 binding activity, and nuclear localization, all in human cell lines. BRCA2 Ile27Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile27Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the PALB2 binding domain (Roy 2012). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a cryptic donor site upstream of the natural splice donor site of exon 3 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Ile27Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000113106 SCV000297559 uncertain significance Breast-ovarian cancer, familial 2 2010-03-09 no assertion criteria provided clinical testing

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