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 2020-01-17 criteria provided, single submitter clinical testing The p.A349P variant (also known as c.1045G>C), located in coding exon 7 of the BRIP1 gene, results from a G to C substitution at nucleotide position 1045. The alanine at codon 349 is replaced by proline, an amino acid with highly similar properties. This alteration was detected in a stillborn fetus delivered at a gestational age of 22 weeks who had distinctive characteristics of severe Fanconi anemia. Genetic analysis revealed that the fetus carried this alteration as well as the p.R798* nonsense mutation in the BRIP1 gene (Levran O et al. Nat. Genet. 2005; 37:931-3). This alteration has also been identified in patients with ovarian cancer in two separate studies (Kanchi KL et al. Nat Commun. 2014; 5:3156; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). Functional studies revealed that this alteration has significantly impaired helicase activity leading to decreased cell survival upon exposure to DNA damaging agents (Wu Y et al. Blood. 2010; 116(19):3780-91; Sommers JA et al. J. Biol. Chem. 2014 Jul; 289(29):19928-41). Furthermore, this alteration is able to act in a dominant-negative fashion in BRIP1-sufficient cells (Wu Y et al. Blood. 2010; 116(19):3780-91). The functional impairment of this alteration is likely due to the disruption of a critical iron-sulfur cluster domain which is conserved in other members of this helicase family of proteins (Rudolf J et al. Mol. Cell. 2006 Sep; 23(6):801-8; internal structural analysis). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on clinical evidence that this variant has been detected in Fanconi anemia and from supporting functional studies, this variant is likely to be pathogenic.
GeneDx RCV000216316 SCV000279247 likely pathogenic not provided 2020-02-25 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect: impairs iron binding and helicase activity, increases sensitivity to DNA damage, exerts a dominant-negative effect (Rudolf 2006, Wu 2010, Nath 2017, Moyer 2020); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26790966, 24728327, 29922827, 24448499, 21345144, 16973432, 25374583, 27107905, 24895130, 20980836, 26596371, 26921362, 28911102, 20639400, 16116424, 30322717, 31822495, 29019354, 33619228)
Invitae RCV000466014 SCV000547344 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2020-09-08 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 individuals with ovarian cancer (PMID: 16116424, 24448499, 31822495, 30322717). 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
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761010 SCV000890925 likely pathogenic Diffuse intrinsic pontine glioma 2016-01-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131544 SCV001357009 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 349 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant protein exhibits the loss of the helicase activity, decreased iron binding, and decreased protein stability and results in reduced cell viability upon exposure to DNA damaging agents (PMID: 16973432, 20639400, 20980836, 23935105, 24895130, 27107905, 28911102, 31822495). This variant has been reported in compound heterozygosity with a pathogenic truncation variant in an individual affected with Fanconi anemia (PMID: 16116426). This variant has also been reported in individuals affected with ovarian cancer (PMID: 24448499, 30322717, 31265121, 31341520). This variant has been identified in 5/282726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251275 SCV001426801 pathogenic Malignant tumor of breast 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
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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