ClinVar Miner

Submissions for variant NM_001114636.1(FANCL):c.1111_1114dup (p.Thr372fs) (rs759217526)

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Total submissions: 8
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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 2019-12-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513086 SCV000331723 pathogenic not provided 2016-02-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Praxis fuer Humangenetik Tuebingen RCV000513086 SCV000608939 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000513086 SCV000748638 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing The c.1096_1099dupATTA variant in the FANCL gene has been reported previously using alternate nomenclature (c.1095_1098dupAATT), in combination with another FANCL variant on the opposite allele (in trans) in an individual with mild features of Fanconi anemia (Ali et al., 2009). This variant has also been reported previously 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). However, some of these individuals were noted to have potentially pathogenic variants in other cancer-related genes (Lhota et al., 2016; Tedaldi et al., 2017). While at least one study found an overrepresentation of this variant in individuals with high-risk breast cancer as compared to controls, this finding has not been replicated in other studies, suggesting that this variant is not likely to be a high risk variant but may modify the risk of breast cancer (Lhota et al., 2016; Pfeifer et al., 2016; Zemankova et al., 2016). The c.1096_1099dupATTA variant causes a frameshift starting with codon Threonine 367, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr367AsnfsX13. This frameshift variant replaces the typical last nine amino acid residues in the FANCL protein with twelve different amino acid residues. This alteration may interfere with the proper formation and/or function of the FANCL protein. Functional studies suggest that this variant is associated with partial FANCL activity (Ali et al., 2009). The c.1096_1099dupATTA variant is observed in 71/10,082 (0.7%) alleles from individuals of Ashkenazi Jewish background and 812/275,410 (0.3%) total alleles, including multiple unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). We interpret c.1096_1099dupATTA as a variant of uncertain significance.
Mendelics RCV000986760 SCV001135876 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
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.

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