ClinVar Miner

Submissions for variant NM_018062.3(FANCL):c.1007_1009del (p.Ile336_Cys337delinsSer) (rs747253294)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479284 SCV000568796 likely pathogenic not provided 2017-03-20 criteria provided, single submitter clinical testing The c.1007_1009delTAT variant in the FANCL gene has been reported previously as compound heterozygous with a frameshift variant in a child with FA who presented with slow growth, poor feeding, irritability, mildly delayed myelination on MRI, ADHD, a single cafe-au-lait spot, mild hypocellularity and a family history of leukemia, but no obvious FA phenotype (Ali et al., 2009). The child's FA diagnosis was achieved by FA complementation assay followed by sequence analysis of FANCL. In vitro functional studies in EUFA868 cells showed this allele resulted in substantial G2/M arrest, lack of FANCD2 monoubiquitination, increased sensitivity to mitomycin C, and a high rate of chromosome breakage; therefore the authors concluded c.1007_1009delTAT was a null allele (Ali et al., 2009). The c.1007_1009delTAT variant results in the loss of two correct amino acids (Isoleucine 336 and Cysteine 337) and the addition of an incorrect amino acid (Serine), denoted p.Ile336_Cys337delinsSer. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret c.1007_1009delTAT as a likely pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000500979 SCV000594738 pathogenic Fanconi anemia, complementation group L 2015-09-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000500979 SCV000914933 likely pathogenic Fanconi anemia, complementation group L 2018-10-25 criteria provided, single submitter clinical testing The FANCL c.1022_1024delTAT (p.Ile341_Cys342delinsSer) variant is an in-frame deletion variant that results in the loss of isoleucine 341 and conversion of cysteine 342 to serine. It has been reported in a compound heterozygous state in two individuals with Fanconi anemia (FA) complementation group L (Ali et al. 2009; Chandrasekharappa et al. 2013) as well as in a cell line derived from an FA patient for whom no additional phenotypic details were available (Raghunandan et al. 2015). The variant was also identified in a heterozygous state in two individuals: a female with breast or ovarian cancer who came from a high-risk family and met guidelines for hereditary cancer risk evaluation (Maxwell et al. 2016) and a 12-year-old boy with bone marrow failure and short telomeres but no congenital anomalies (Zhang et al. 2015). Collet et al. (2015) identified the p.Ile341_Cys342delinsSer variant in one of 71 non-cancer control individuals, and the variant is reported at a frequency of 0.000627 in the European American population of the Genome Aggregation Database. Expression of the variant protein in a cell line lacking the FANCL protein was unable to rescue the phenotype of G2/M arrest, absent mono-ubiquitination with FANCD2, increased sensitivity to mitomycin C and a high rate of chromosome breakage, suggesting the variant impairs protein function (Ali et al. 2009).Based on the collective evidence, the p.Ile341_Cys342delinsServariant is classified as likely pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000228349 SCV000290414 uncertain significance Fanconi anemia 2018-07-30 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 12 of the FANCL mRNA (c.1007_1009delTAT). This leads to the replacement of 2 amino acid residues in the FANCL protein by a non-related serine residue (p.Ile336_Cys337delinsSer) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs747253294, ExAC 0.05%). This variant has been reported in two unrelated individuals affected with Fanconi anemia (FA) (PMID: 19405097, 23613520). In one of these individuals, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant (PMID: 19405097). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 241247). Experimental studies have shown that this missense change abolishes the binding of FANCL to FANCA, FANCG, FAAP100 and FANCM, and is not able to rescue FANCL null cells (PMID: 19405097). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000228349 SCV000966835 likely pathogenic Fanconi anemia 2019-01-04 criteria provided, single submitter clinical testing The p.Ile341_Cys342delinsSer variant in FANCL has been reported in the compound heterozygous state in 2 individuals with Fanconi anemia (Ali 2009, Chandrasekhar appa 2013). It has also been identified in 0.06% (80/128464) of European chromos omes by gnomAD (http://gnomad.broadinstitute.org). This variant results in a del etion of 3 base pairs that results in the removal of 2 amino acids and introduct ion of a serine (Ser) at position 341 and is not predicted to alter the protein reading-frame. In vitro functional studies, including a complementation assay, s upport an impact on protein function (Ali 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Fa nconi anemia. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PM2_Supporting, PM4_ Supporting.
Molecular Development Laboratory,Murdoch Childrens Research Institute RCV000766177 SCV000882511 uncertain significance Premature ovarian insufficiency 2018-01-10 no assertion criteria provided research

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