ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9995_9996CT[1] (p.Leu3333fs) (rs730881621)

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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 RCV000217081 SCV000275079 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000766660 SCV000210814 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9997_9998delCT at the cDNA level and p.Leu3333PhefsX4 (L333FfsX4) at the protein level. This variant, also defined as BRCA2 10225_10226delCT using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. The surrounding sequence with the bases deleted in brackets is TTCT[delCT]TTTG. The deletion causes a frameshift, changing a Leucine to an Phenylalanine at codon 3333, and creating a premature stop codon at position 4 of the new reading frame. Although this variant results in a premature stop codon, it is located downstream of a well-known polymorphism that also results in a premature stop of translation (Lys3326Ter), suggesting that the region of the BRCA2 gene beyond codon 3326 is not crucial for proper function. Based on currently available evidence, it is unclear whether BRCA2 c.9997_9998delCT is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000160318 SCV000695285 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9997_9998delCT (p.Leu3333PhefsX4) results in a premature termination codon in the last exon of the protein, predicted to cause the truncation of the C-terminal end of the protein that does not belong to any known functional domain. This variant is located downstream of a well-known polymorphism c.9976A>T (p.Lys3326X), that results in a truncated protein, suggesting that the region of the BRCA2 gene beyond codon 3326 is not crucial for proper function. The variant allele was found at a frequency of 6.5e-05 in 30984 control chromosomes (in gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs. 0.00075), allowing no conclusion about variant significance. c.9997_9998delCT has been reported in the literature in an individual affected with medulloblastoma (Waszak 2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with classifications ranging from VUS (2x) to likely benign (1x). The variant was identified in an internal sample in an unaffected individual undergoing genetic screening because of positive family history (mother, sister, maternal great aunt, all diagnosed with early onset Breath Cancer; brother diagnosed with Non-Hodgkin Lymphoma at age of 37). However, testing information on the family members to rule in or rule out co-segregation with disease was not available. On the other hand, a co-occurrence with a pathogenic BRCA1 variant has also been reported in another internal sample (BRCA1 c.5324T>G (p.Met1775Arg)), providing supporting evidence for a benign role. Based on the evidence outlined above, the variant was classified as a VUS-possibly benign.
Invitae RCV000472705 SCV000560400 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-29 criteria provided, single submitter clinical testing

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