ClinVar Genomic variation as it relates to human health

This variant is a single amino acid change from Arginine to a Termination codon at amino acid residue 798 of the BRIP1 gene. It results in a truncated non-functional protein. This variant has been reported to segregate with disease in families affected with Fanconi anemia (PMID: 16116423, 16116424). It has also been seen in individuals affected with ovarian cancer (PMID: 24240112) and suspected Lynch syndrome (PMID: 25980754), as well as in individuals and families with breast cancer (PMID: 17033622, 19763819, 26822949) and prostate cancer (PMID: 19127258, 24556621). The mutation database ClinVar contains entries for this variant (Variation ID: 4738).

The c.2392C>T variant results in the introduction of a premature stop codon at residue 798 (p.Arg798X). This variant is predicted to generate an unstable transcript, targeted for degradation by nonsense-mediated mRNA decay. Loss of function variants in BRIP1 are known to be pathogenic. The c.2392C>T variant (also reported in the literature as c.2533C>T) has been reported in individuals affected with ovarian cancer (Pennington 2014) and suspected Lynch syndrome (Yurgelun 2015), as well as in individuals and families with breast cancer (Seal 2006; Lhota 2016). Based on current evidence, the c.2392C>T variant is classified as pathogenic.

Variant summary: BRIP1 c.2392C>T (p.Arg798X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00018 in 369611 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Fanconi Anemia Complementation Group J (0.0004), allowing no conclusion about variant significance. In addition, this variant has also been reported in 6 / 9884 women who were older than age 70, and cancer free (in the FLOSSIES database). The variant, c.2392C>T, has been reported in the literature in multiple homozygous- or compound heterozygous individuals affected with Fanconi Anemia Complementation Group J (e.g. Levitus_2005, Levran_2005), as well as in heterozygous individuals affected with ovarian cancer, breast cancer, prostate cancer, and other tumor phenotypes (e.g. Seal_2006, Kote-Jarai_2009, Rafnar_2011, Yurgelun_2015, Susswein_2016). Large case-control studies evaluating this variant among breast cancer (BrC) cases and controls in the Breast Cancer Association Consortium (BCAC), reported weak- or no association with familial breast cancer (Easton_2016, Dorling_2021). However, a recent meta-analysis found a moderate risk for ovarian cancer (OR=2.22, 95% CI: 1.20-4.11; p < 0.0001; Suszynska_2020). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated defective ATP hydrolysis and the loss of helicase activity (e.g. London_2008, Barthelemy_2016). Twenty-one other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=19) / likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant could be a moderate risk allele for ovarian cancer, and it was classified as pathogenic in the context of Fanconi Anemia complementation group J.

The BRIP1 c.2392C>T variant is classified as Pathogenic (PVS1, PS4, PM3)

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

This variant causes the premature termination of BRIP1 protein synthesis. In the published literature, it has been reported in the heterozygous state in individuals with ovarian cancer, breast cancer, prostate cancer, and suspected Lynch syndrome (PMID: 26822949 (2016), 26315354 (2015), 25980754 (2015), 24556621 (2014)). It has also been reported in the homozygous or compound heterozygous state as a recurrent mutation in individuals with Fanconi Anemia type J (PMID: 26968956 (2016), 16116424 (2005), 16116423 (2005)). Consistent with a role of heterozygous pathogenic BRIP1 variants primarily in predisposition to ovarian cancer, this variant was not associated with a substantial increase in breast cancer risk in a case-control study (PMID: 26921362 (2016)). The variant was associated with decreased protein expression in experimental studies (PMID: 16153896 (2005)). Based on the available information, the variant is classified as pathogenic.

The c.2393C>T (p.Arg798Ter) variant is a stop-gained variant, described in three studies in which it is found in 18 Fanconi anemia patients, including 11 in a homozygous state, three in a compound heterozygous state, and in five alleles of unspecified zygosity (Levitus et al. 2005; Levran et al. 2005; Ghazwani et al. 2016). The p.Arg798Ter variant was absent from 50 controls but is reported at a frequency of 0.00024 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Arg798Ter variant is classified as pathogenic for Fanconi anemia.

The BRIP1 c.2392C>T (p.Arg798Ter) variant, also known as c.2533C>T, is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg798Ter variant has been reported in at least seven studies in which it is found in a total of 27 individuals, including in a homozygous state in 12 individuals with Fanconi anemia (FA), in a compound heterozygous state in five individuals with FA, and in a heterozygous state in six individuals with prostate cancer, in two with ovarian cancer, and in one with endometrioid cancer, and in unknown zygosity in one individual with FA (Levran et al. 2005; Levitus et al. 2005; Kote-Jarai et al. 2009; Leongamornlert et al. 2014; Pennington et al. 2014; Ramus et al. 2015; Ghazwani et al. 2016). The variant is noted to segregate with disease in four families with FA (Levran et al. 2005; Levitus et al. 2005). The p.Arg798Ter variant was identified in a heterozygous state in one of 4090 control alleles and is reported at a frequency of 0.000280 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg798Ter variant is classified as pathogenic for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The c.2392C>T;p.(Arg798*) variant creates a premature translational stop signal in the BRIP1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4738; PMID: 16116423; 16116424; 17033622; 19127258; 19763819; 24240112; 24556621; 25980754; 26822949; 26968956) - PS4. The variant is present at low allele frequencies population databases (rs137852986 – gnomAD 0.001581%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg798*) was detected in trans with a pathogenic variant (PMID: 16116423; 16116424; 26968956). PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16116423; 16116424) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

PVS1, PM3_Strong

The BRIP1 c.2392C>T (p.Arg798Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Fanconi anemia (PM3; PMID: 16116423, 16116424). It has also been reported in the heterozygous state in individuals and families with breast cancer (PMID: 17033622, 19763819, 26822949), prostate cancer (PMID: 19127258, 24556621), and ovarian cancer (PMID: 24240112). This variant has a maximum subpopulation frequency of 0.027% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PM3.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the heterozygous state in individuals with BRIP1-related and other cancers (Seal 2006, Kote-Jarai 2009, McInerney 2010, Pennington 2014, Ramus 2015, Lhota 2016, Thompson 2016, Tung 2016, Frey 2017); This variant is associated with the following publications: (PMID: 26315354, 16153896, 27869810, 28495237, 26786923, 16116424, 24240112, 26556299, 25070891, 25980754, 25583207, 17033622, 27107905, 18978354, 27179029, 26136524, 19127258, 24556621, 26822949, 26921361, 26720728, 27734215, 16116423, 23613520, 27210295, 26968956, 19763819, 26709662, 26976419, 28558075, 28418444, 26921362, 26681312, 29368626, 22006311, 28125078, 26580448, 28796317, 28709830, 28008555, 28873162, 28152038, 25186627, 29753700, 31124294, 30982232, 30322717, 31159747, 25525159, 34026625, 34426522, 33077847, 32885271, 32338768, 32427313, 33258288, 31742824, 32830346)

ACMG classification criteria: PVS1 very strong, PS3 supporting, PM3 very strong

This sequence change creates a premature translational stop signal (p.Arg798*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs137852986, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 16116423, 16116424, 17033622, 19127258, 19763819, 24240112, 24556621, 25980754, 26822949). It has also been observed to segregate with disease in related individuals. This variant is also known as 2533C>T. ClinVar contains an entry for this variant (Variation ID: 4738). For these reasons, this variant has been classified as Pathogenic.

The stop gained c.2392C>T (p.Arg798Ter) variant has been reported to segregate with disease in families affected with Fanconi anemia (Levitus M et al., 2005). The p.Arg798Ter variant is reported with the allele frequency (0.016 %) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2392C>T in BRIP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

PP4, PM3_strong, PS4_moderate, PVS1

This variant changes 1 nucleotide in exon 17 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that the mutant transcript undergoes nonsense-mediated decay (PMID: 26921362). This variant has been reported in individuals affected with ovarian cancer (PMID: 24240112), breast cancer (PMID: 17033622, 19763819, 26822949, 32068069, 3375802), prostate cancer (PMID: 19127258, 24556621), and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). Case-control studies have suggested that this variant is associated with a mild increase in ovarian cancer risk (PMID: 32359370) and a mild increase in estrogen receptor-negative and triple-negative breast cancer risk, but not overall breast cancer risk (PMID: 26921362). This variant has also been reported in homozygous state and in compound heterozygous state with another BRIP1 pathogenic variant in individuals affected with Fanconi anemia (PMID: 16116423, 16116424, 26968956). This variant has been identified in 44/278320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The BRIP1 c.2392C>T; p.Arg798Ter variant (rs137852986) is reported in the literature in individuals with ovarian cancer, breast cancer, colorectal cancer, prostate cancer, medulloblastoma, or Ewing sarcoma (Brohl 2017, Leongamornlert 2014, Lhota 2016, Waszak 2018, Weber-Lassalle 2018, Yurgelun 2015). It is also reported in individuals with Fanconi anemia when found in the homozygous state or as compound heterozygous with an additional pathogenic BRIP1 variant (Levitus 2005). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 4738). It is found in the general population with an overall allele frequency of 0.02% (44/278320 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Brohl AS et al. Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. Genet Med. 2017 Aug;19(8):955-958. Leongamornlert D et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer. 2014 Mar 18;110(6):1663-72. Levitus M et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005 Sep;37(9):934-5. Lhota F et al. Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. Clin Genet. 2016 Oct;90(4):324-33. Waszak SM et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol. 2018 Jun;19(6):785-798. Weber-Lassalle N et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018 Jan 24;20(1):7. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

This sequence change creates a premature translational stop signal (p.Arg798*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs137852986, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 16116423, 16116424, 17033622, 19127258, 19763819, 24240112, 24556621, 25980754, 26822949). It has also been observed to segregate with disease in related individuals. This variant is also known as 2533C>T. ClinVar contains an entry for this variant (Variation ID: 4738). For these reasons, this variant has been classified as Pathogenic.

The p.R798* pathogenic mutation (also known as c.2392C>T), located in coding exon 16 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2392. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration has been described as a recurrent disease causing mutation in both Fanconi anemia type-J (FA-J) and breast cancer patients (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5; Levran O et al. Nat. Genet. 2005 Sep;37:931-3; Seal S et al. Nat. Genet. 2006 Nov;38:1239-41; McInerney NM et al. Breast Cancer Res. Treat. 2010 May;121:203-10; Doddato G et al. Front Oncol 2021 May;11:649435). In addition, this mutation has been detected in prostate and ovarian cancer cohorts (Kote-Jarai Z et al. Br. J. Cancer. 2009 Jan;100:426-30; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Leongamornlert D et al. Br. J. Cancer. 2014 Mar;110:1663-72; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879; Flaum N et al. Clin Genet 2022 01;101(1):48-54). Of note, this alteration is also designated as p.Arg1035X in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

BRIP1: PVS1, PS4

The BRIP1 c.2392C>T variant is predicted to result in premature protein termination (p.Arg798*). This variant (also described as c.2533C>T in the literature) has been reported in the homozygous or compound heterozygous state in individuals with Fanconi anemia (Levran et al. 2005. PubMed ID: 16116424; Shamseldin et al. 2021. PubMed ID: 34645488). This variant has been reported, in the heterozygous state or in combination with another possible pathogenic variant in a different gene, in individuals with ovarian cancer (Pennington et al. 2014. PubMed ID: 24240112), breast cancer (Lhota et al. 2016. PubMed ID: 26822949; Lerner-Ellis et al. 2021. PubMed ID: 32885271), colorectal cancer (Susswein et al. 2016. Table S1, PubMed ID: 26681312), renal cell carcinoma (Smith et al. 2021. PubMed ID: 32830346), and familial and sporadic prostate cancers (Kote-Jarai et al. 2009. PubMed ID: 19127258). However, a recent large study of individuals predominantly of European origin, including 48,144 breast cancer cases and 43,607 controls, reported that the c.2392C>T (p.Arg798*) variant was present at similar frequencies in cases and controls. Similarly, other truncating variants were also reported at similar frequencies in cases and controls. The authors concluded that truncating variants in BRIP1, and the c.2392C>T (p.Arg798*) variant in particular, have no significant association with breast cancer risk (Easton et al. 2016. PubMed ID: 26921362). However, there was weak evidence of increased risk of estrogen receptor (ER)-negative and triple-negative breast cancers in individuals with the c.2392C>T (p.Arg798*) variant. The c.2392C>T (p.Arg798*) variant has been observed in 44/278320 alleles (~0.016%) within a database of individuals of unknown phenotype and is interpreted as pathogenic or likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4738/). Based on the available data, this variant is pathogenic for Fanconi anemia and several cancers; however, the evidence for its risk for developing breast cancer is not as strong.

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Zdenek Kleibl.

The BRIP1 p.Arg798X variant was identified in 31 of 118976 proband chromosomes (frequency: 0.0003) from families with high risk BRCA1/2/PALB2 negative breast cancer, early-onset or familial breast cancer, ovarian cancer, Lynch syndrome, prostate cancer, or triple negative breast cancer and was identified in 3 of 102538 control chromosomes from healthy individuals (frequency: 0.00003, Lhota 2016, McInerney 2010, Seal 2006, Yurgelun 2015, Kote-Jarai 2009, Leongamornlert 2014, Ramus 2015, Couch 2015). Segregation studies in 1 proband with prostate cancer showed partial segregation of the variant with disease, with 1 affected sibling carrying the variant and the other affected sibling testing negative (Kote-Jarai 2009). Analysis of the variant protein, from lymphoblastoid cell lines, by immunoblotting showed an absence of the protein in both homozygous and heterozygous carriers and absence of homologous recombination (Levran 2005, Litman 2005). cDNA sequencing of 1 proband with Fanconi anemia carrying the variant with a co-occurring BRIP1 variant (IVS17+2insT), identified 3 mRNA transcripts, 2 lacking either exon 17 or 18 and both leading to a frameshift yielding a partial deletion of the helicase motif and BRCA1 binding site (Levitus 2005). The variant was also identified in dbSNP (ID: rs137852986) as “With Pathogenic allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: pathogenic by GeneDx, Ambry Genetics, Invitae, and 5 additional submitter, as Likely pathogenic by Counsyl, and uncertain significance by Illumina), Cosmic (1x in carcinoma of salivary gland), Zhejiang University Database (20x) and was not identified in MutDB. The variant was identified in control databases in 45 of 273100 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 35 of 125106 chromosomes (freq: 0.0003), the African population in 1 of 23852 chromosomes (freq: 0.00004), “Other” in 2 of 6376 chromosomes (freq: 0.0003), Latino in 4 of 33846 chromosomes (freq: 0.0001), East Asian in 1 of 18232 chromosomes (freq: 0.00006), and South Asian in 2 of 30042 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, and Finnish populations. The c.2392C>T variant is predicted to lead to a premature stop codon at amino acid position 798 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRIP1 gene are an established mechanism of disease in BRIP1 associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant is classified as pathogenic.

Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/20/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.