ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9676del (p.Tyr3226fs) (rs80359774)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000114152 SCV000301409 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000114152 SCV000328161 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482822 SCV000564804 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.9676delT at the cDNA level and p.Tyr3226IlefsX23 (Y3226IfsX23) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATAT[delT]ATCA. The deletion causes a frameshift which changes a Tyrosine to an Isoleucine at codon 3226, and creates a premature stop codon at position 23 of the new reading frame. BRCA2 c.9676delT, also known as 9904delT using alternate nomenclature, has been observed in at least one individual with a personal and family history of breast cancer (Pilato 2016). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 193 amino acids are replaced with 22 incorrect amino acids. The disrupted region at the end of the gene impacts the two nuclear localization signals (NLS1 and NLS2), as well as Cyclin A and RAD51 binding and various phosphorylated residues (Esashi 2005, Bahassi 2008, Borg 2010, Roy 2012). Based on currently available evidence, we consider this deletion to be a likely pathogenic variant.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114152 SCV000147697 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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