ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1045G>C (p.Ala349Pro) (rs149364097)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131544 SCV000186543 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-09 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Structural Evidence;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Deficient protein function by in vitro/ex vivo assay;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000216316 SCV000279247 likely pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1045G>C at the cDNA level, p.Ala349Pro (A349P) at the protein level, and results in the change of an Alanine to a Proline (GCC>CCC). Functional assays have shown this variant to impact iron binding, abolish helicase activity, and exert a dominant-negative effect via cell survival and gamma-H2AX foci formation assays (Rudolf 2006, Wu 2010). Kanchi et al. (2014) observed BRIP1 Ala349Pro once in the heterozygous state in a series of 387 ovarian cancer cases but not in 557 controls. In addition, Levran et al. (2005) observed this variant in the compound heterozygous state with a BRIP1 nonsense variant in an individual with Fanconi anemia. BRIP1 Ala349Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider BRIP1 Ala349Pro to be a likely pathogenic variant.
Invitae RCV000466014 SCV000547344 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 349 of the BRIP1 protein (p.Ala349Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs149364097, ExAC 0.02%). This variant has been reported in a compound heterozygous state on the opposite chromosome with a pathogenic variant (p.Arg798*) in an individual affected with Fanconia anemia, and has been reported in the heterozygous state in an individual affected with ovarian cancer (PMID: 16116424, 24448499). This variant is also known as (c.1186G>C) in the literature. ClinVar contains an entry for this variant (Variation ID: 30535). Experimental studies have shown that this missense change, which is located in the metal binding domain, destabilizes the Fe-S cluster, abolishes helicase activity, and exerts a dominant-negative effect, indicating that the mutant protein interferes with normal DNA metabolism (PMID: 16973432, 20639400, 27107905). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics,PreventionGenetics RCV000216316 SCV000807119 likely pathogenic not provided 2017-09-23 criteria provided, single submitter clinical testing
Color RCV000131544 SCV001357009 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251275 SCV001426801 pathogenic breast cancer 2020-07-16 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1045G>C (p.Ala349Pro) results in a non-conservative amino acid change located in the Fe-S domain in the helicase core (Moyer_2019) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 259476 control chromosomes (gnomAD and publications). c.1045G>C has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Kanchi_2014, Carter_2018, Zhu_2019, Moyer_2019). In addition, this variant has been reported in a compound heterozygous state with another pathogenic BRIP1 variant (p.R798X) in one individual affected with Fanconi anemia (Levran_2005). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies report A349P affects protein function based on abolished the helicase activity, DNA binding activity, translocase activity and effects of MMC on chromosome fragmentation, cell viability, and cell cycle, but has normal protein stability (Rudolf_2006, Wu_2009, Guo_2016, Sommers_2014, Moyer_2019). Six ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000023492 SCV000044783 pathogenic Fanconi anemia, complementation group J 2010-11-11 no assertion criteria provided literature only
ITMI RCV000120412 SCV000084564 not provided not specified 2013-09-19 no assertion provided reference population
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761010 SCV000890925 likely pathogenic Diffuse intrinsic pontine glioma 2016-01-15 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000023492 SCV001364493 pathogenic Fanconi anemia, complementation group J 2011-02-07 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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