ClinVar Miner

Submissions for variant NM_018062.4(FANCL):c.1096_1099dup (p.Thr367fs)

dbSNP: rs759217526
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000192919 SCV000247355 uncertain significance not specified 2019-08-02 criteria provided, single submitter clinical testing
Invitae RCV000226300 SCV000290416 benign Fanconi anemia 2021-12-17 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000513086 SCV000331723 pathogenic not provided 2016-02-24 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000226300 SCV000431329 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing The c.1111_1114dupATTA (p.Thr372AsnfsTer13) variant, which results in a frameshift near the C-terminus of the protein and extends the full-length protein by ten amino acids, was observed in a patient with clinical features suggestive of Fanconi anemia (Ali et al. 2009). This patient was compound heterozygous for the p.Thr372AsnfsTer13 variant, which was inherited from the patient's father, and a second inframe deletion variant that was inherited from the patient's mother. Functional testing of this variant, when ectopically expressed in FA-L patient cell line, resulted in a phenotype intermediate of EUFA868 cells expressing vector alone and EUFA868 cells expressing wild-type FANCL. The p.Thr372AsnfsTer13 variant has been reported at a frequency of 0.00783 in the population described as 'Other' in the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Thr372AsnfsTer13 variant is classified as a variant of uncertain significance but suspicious for pathogenicity for Fanconi anemia.
CeGaT Center for Human Genetics Tuebingen RCV000513086 SCV000608939 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000513086 SCV000748638 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation as the last 9 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in the heterozygous state, sometimes using alternate nomenclature (c.1095_1098dupAATT, c.1094_1095insAATT, or c.1100_1100C>ATTAC), in multiple individuals with cancer, including breast cancer, head and neck squamous cell carcinoma, childhood-onset solid tumors, and lung adenocarcinoma (Akbari et al., 2011; Ellingson et al., 2015; Lhota et al., 2016; Parsons et al., 2016; Tedaldi et al., 2017; Chandrasekharappa et al., 2017; Ghazani et al., 2017); This variant is associated with the following publications: (PMID: 33504652, 32235514, 30306255, 26296701, 28678401, 28125075, 28423363, 26822237, 27659787, 27506598, 26822949, 21279724, 19405097, 27153395)
Mendelics RCV000986760 SCV001135876 uncertain significance Fanconi anemia complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001195069 SCV002011559 uncertain significance Fanconi anemia complementation group L 2021-11-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192919 SCV002103929 benign not specified 2022-02-22 criteria provided, single submitter clinical testing Variant summary: FANCL c.1096_1099dupATTA (p.Thr367AsnfsX13) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.003 in 249062 control chromosomes in the gnomAD database, including 4 homozygotes. Truncations downstream of this variant have not been observed at our laboratory and not reported in association with Fanconi Anemia in the HGMD/LOVD database. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCL causing Fanconi Anemia phenotype (0.00028), strongly suggesting that the variant is benign. Although widely reported in the literature, to our knowledge, no penetrant association of c.1096_1099dupATTA in individuals affected with Fanconi Anemia and no supporting experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and one submitter reporting a pathogenic classification has since re-classified it internally as Benign (Benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001195069 SCV002320677 uncertain significance Fanconi anemia complementation group L 2021-04-28 criteria provided, single submitter clinical testing FANCL NM_018062.3 exon 14 p.Thr367Asnfs*13 (c.1096_1099dup): This variant has been reported in the literature in the compound heterozygous state in one individual with mild features of fanconi anemia (Ali 2009 PMID:19405097). It has also been reported in the heterozygous state in association with multiple different types of cancers (breast, lung adendocarcinoma, pediatric solid tumors, esophageal, head and neck squamous cell carcinoma) (Akbari 2011 PMID:21279724, Lhota 2016 PMID:26822949, Parsons 2016 PMID:26822237, Chandrasekharappa 2017 PMID:28678401, Ghazani 2017 PMID:28125075, del Valle 2020 PMID:32235514). However, this variant is also present in 0.4% (287/67948) of European alleles in the Genome Aggregation Database, including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-58159793-G-GTAAT?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:210989). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a frameshift variants that removes the final termination codon and extends out the protein. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Sema4,Sema4 RCV000226300 SCV002527272 likely benign Fanconi anemia 2021-06-04 criteria provided, single submitter curation
Daryl Scott Lab,Baylor College of Medicine RCV001195069 SCV002567936 uncertain significance Fanconi anemia complementation group L 2022-08-22 criteria provided, single submitter clinical testing
OMIM RCV001195069 SCV000044971 pathogenic Fanconi anemia complementation group L 2009-07-01 no assertion criteria provided literature only
Leiden Open Variation Database RCV001195069 SCV001365354 likely pathogenic Fanconi anemia complementation group L 2019-07-20 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Zdenek Kleibl.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000513086 SCV001800208 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000513086 SCV001806996 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000513086 SCV001953664 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000513086 SCV001973305 uncertain significance not provided no assertion criteria provided clinical testing

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