ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2255_2256del (p.Lys752fs) (rs730881649)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212320 SCV000210871 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRIP1 c.2255_2256delAA at the cDNA level and p.Lys752ArgfsX12 (K752RfsX12) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAGA[delAA]Ggta, where the capital letters are exonic and lowercase are intronic. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 752, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRIP1 c.2255_2256delAA, also reported as BRIP1 c.2255delAA, has been observed in individuals with breast and/or ovarian cancer as well as in the compound heterozygous state in an individual with Fanconi Anemia (Levitus 2005, Seal 2006, Ramus 2015, Tung 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000160364 SCV000214477 pathogenic Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000167986 SCV000218635 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys752Argfs*12) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881649, ExAC 0.003%). This variant has been observed in an individual with Fanconi anemia (PMID: 16116423), and in individuals with ovarian cancer or breast cancer (PMID: 26315354, 26681312, 26681682, 26976419). This variant is also known as c.2255_2256delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 182372). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.
Color RCV000160364 SCV000292165 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587824 SCV000699686 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60679), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRIP1 variant of 1/16000. In addition, this observation needs to be cautiously considered due to the cohort including individuals that could harbor a BRIP1 phenotype. The variant of interest has been reported in affected individuals with varying phenotypes BrC, OvC and FANCJ, including the variant of interest segregating with disease (BrC) within one family (Seal_2006). In addition, multiple reputable clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Counsyl RCV000662905 SCV000785827 pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2017-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212320 SCV001134013 pathogenic not provided 2019-03-27 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.

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