ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2390A>G (p.Lys797Arg) (rs730881622)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212323 SCV000210816 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2390A>G at the cDNA level, p.Lys797Arg (K797R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has been observed to co-occur in trans with a known pathogenic variant in an individual diagnosed with Fanconi Anemia (Chandrasekharappa 2013). BRIP1 Lys797Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Lys797Arg occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Lys797Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160319 SCV000216023 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000477092 SCV000547294 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 797 of the BRIP1 protein (p.Lys797Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26921362). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Fanconi anemia (PMID: 23613520). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 182330). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663309 SCV000786568 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-05-24 criteria provided, single submitter clinical testing
Color RCV000160319 SCV000903895 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781178 SCV000919058 uncertain significance not specified 2018-06-22 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2390A>G (p.Lys797Arg) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 119316 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2390A>G, has been reported in the literature in an individual affected with Breast Cancer (Easton 2016), but was also reported in a healthy individual older than 70 years who has never had cancer (FLOSSIES). The variant has been reported in an individual affected with Fanconi Anemia, with a known pathogenic BRIP1 variant in trans (Chandrasekharappa 2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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