ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2400C>G (p.Tyr800Ter) (rs574552037)

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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 RCV000131417 SCV000186395 pathogenic Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000254652 SCV000210817 pathogenic not provided 2018-02-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRIP1 c.2400C>G at the cDNA level and p.Tyr800Ter (Y800X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as BRIP1 2541C>G using alternate nomenclature, has been observed in an individual with peritoneal cancer, another with a personal history of ovarian cancer and family history of breast and ovarian cancer, and was also reported in the compound heterozygous state with a second truncating BRIP1 variant in an individual with Fanconi anemia (Norquist 2015, Ramus 2015, Levran 2005). We consider this variant to be pathogenic.
Invitae RCV000205848 SCV000260437 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr800*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs574552037, ExAC 0.005%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Fanconi anemia type J (PMID: 16116424). It has also been reported in an individual affected with ovarian cancer (PMID: 26315354). This variant is also known as 2541C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 142343). 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 RCV000131417 SCV000684211 pathogenic Hereditary cancer-predisposing syndrome 2016-09-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588697 SCV000699692 pathogenic Fanconi anemia, complementation group J 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2400C>G (p.Tyr800X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120180 control chromosomes at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). This variant has been reported in one FA patient with BRIP1 R798X in trans, and no BRIP1 protein was detected in the cells extracts from individual with this variant (Levran_2005). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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