NM_018062.4:c.1007_1009delTAT
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4_SupportingPP5BS1_Supporting
The NM_018062.4(FANCL):c.1007_1009delTAT(p.Ile336_Cys337delinsSer) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,594,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_018062.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
Publications
- Fanconi anemia complementation group LInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCL | NM_018062.4 | c.1007_1009delTAT | p.Ile336_Cys337delinsSer | disruptive_inframe_deletion | Exon 12 of 14 | ENST00000233741.9 | NP_060532.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000329 AC: 50AN: 151846Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000307 AC: 77AN: 250564 AF XY: 0.000325 show subpopulations
GnomAD4 exome AF: 0.000566 AC: 817AN: 1443078Hom.: 0 AF XY: 0.000555 AC XY: 399AN XY: 719070 show subpopulations
Age Distribution
GnomAD4 genome 0.000329 AC: 50AN: 151846Hom.: 0 Cov.: 32 AF XY: 0.000324 AC XY: 24AN XY: 74158 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Fanconi anemia complementation group L Pathogenic:7Uncertain:1
- -
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. -
The inframe deletion c.1007_1009del p.Ile336_Cys337delinsSer variant in FANCL gene has been observed in compound heterozygous state in individuals with bone marrow failure syndromes and / or Fanconi anemia Guidugli et. al., 2017; Chandrasekharappa et. al., 2013. Experimental studies have shown that this variant affects FANCL function Ali et. al., 2009. The observed variant has allele frequency of 0.03% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. This p.Ile336_Cys337delinsSer causes deletion of amino acid Isoleucine at position 336 to Cysteine at position 337. For these reasons, this variant has been classified as Pathogenic. -
- -
- -
FANCL NM_018062.3 exon 12 p.Ile336_Cys337delinsSer (c.1007_1009del): This variant has been reported in the literature in the compound heterozygous state in 2 individuals diagnosed with Fanconi anemi (FA), including one in trans with a pathogenic variant (Ali 2009 PMID:19405097; Chandrasekharappa 2013 PMID:23613520). Of note, one individual did not have clinical features typical of FA (Ali 2009 PMID:19405097). This variant has also been reported in the heterozygous state in an individual with bone marrow failure and short telomeres (Zhang 2015 PMID:25239263). This variant is present in 0.06% (41/67840) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-58161532-CATA-C?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with classifications ranging from Uncertain significance to pathogenic (Variation ID:241247). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein (Ali 2009 PMID:19405097). However, these studies may not accurately represent in vivo biological function. This variant represents an in-frame deletion, with 2 amino acids at positions 336 (Isoleucine) and 337 (Cysteine) removed and replaced by a Serine, and is not predicted to alter the reading frame. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -
The FANCL c.1022_1024del (p.Ile341_Cys342delinsSer) change involves the deletion of three nucleotides at positions 1022-1024 within the RING domain of exon 12, leading to the replacement of two amino acid residues, Ile341 and Cys342, with a serine. This variant has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. An in-vitro assay using a FANCL-deficient cell line showed that the mutated FANCL expression was unable to rescue the phenotype of G2/M cell cycle arrest, showed absence of mono-ubiquitination with FANCD2 thereby failing to activate downstream components of DNA repair pathway, and showed increased sensitivity to mitomycin C (PMID: 19405097). While these findings implicate loss of FANCL function, it is imperative to note the absence of a positive control, thus limiting definitive functional evidence. This variant was reported as compound heterozygous in an individual with Fanconi anemia co-occurring with a deep intronic variant (c.375-2033C>G) with apparent splicing effect (PMID: 23613520). It was also reported in an individual lacking typical phenotypic features corresponding to Fanconi anemia and reported as compound heterozygote with a likely non-deleterious variant (p.Thr367Asnfs*13) (PMID: 19405097). Other studies detected this variant in individuals with precursor B-cell lymphoblastic leukemia, MSI-colorectal cancer, and breast cancer (PMID: 33332384, 36119527, 36356413). This variant is also known as p.Ile336_Cys337delinsSer in the literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
This variant has been previously reported in conjunction with another variant in individuals with features of Fanconi anemia (PMID: 19405097, 23613520, 25239263). It has also been reported in conjunction with another variant in an individual with inherited bone marrow failure (PMID: 28104920). Additionally, this variant has been described in individuals with various cancers (PMID: 29641532, 32191290, 33332384, 34308104, 35988656, 36119527, 36773602) as well as in individuals with hematological malignancies or abnormalities (PMID: 33332384, 29891941, 28104920). Experimental studies demonstrated that this variant impact the protein function (PMID: 19405097, 25659033). -
not provided Pathogenic:3Uncertain:1
Reported as compound heterozygous with a frameshift variant in a child who was diagnosed with Fanconi anemia on the basis of a complementation assay 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 other features associated with Fanconi anemia (PMID: 19405097); Observed as compound heterozygous with a deep intronic variant which was predicted to result in abberant splicing in a sample from the International Fanconi anemia registry (PMID: 23613520); Published functional studies demonstrate a damaging effect: 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 (PMID: 19405097); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of two amino acids and insertion of one incorrect amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 25659033, 19405097, 34308104, 28104920, 31980526, 27153395, 25239263, 23613520) -
FANCL: PM3, PS3:Moderate, PM2:Supporting, PM4:Supporting -
- -
Classification criteria: PM2_Supporting, PM3, PS3 -
Fanconi anemia Pathogenic:1Uncertain:1
This variant, c.1007_1009del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the FANCL protein (p.Ile336_Cys337delinsSer). This variant is present in population databases (rs747253294, gnomAD 0.06%). This variant has been observed in individual(s) with Fanconi anemia and/or osteosarcoma, Fanconi anemia and bone marrow failure syndromes (PMID: 19405097, 23613520, 28104920, 32191290, 34308104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 241247). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FANCL function (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. -
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. -
not specified Uncertain:1
Variant summary: FANCL c.1007_1009delTAT (p.Ile336_Cys337delinsSer) results in an in-frame deletion that is predicted to delete an isoleucine and cysteine and replace with a serine. The variant allele was found at a frequency of 0.00031 in 250564 control chromosomes (gnomAD), predominantly at a frequency of 0.00062 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCL causing Fanconi Anemia (0.00028), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1007_1009delTAT has been reported in the literature as a biallelic genotype in individuals affected with Fanconi Anemia (e.g. Ali_2009, Chandrasekharappa_2013, Raghunandan_2015). The variant was also found in the heterozygous state in individuals affected with breast/ovarian cancer (Maxwell_2016) and bone marrow failure (Guidugli_2017). These data indicate that the variant may be associated with disease. A complementation assay using a FANCL deficient cell line showed that when the variant was overexpressed in this deficient cell line, there was no recovery of FANCL activity, indicating a total loss of function (Ali_2009). The following publications have been ascertained in the context of this evaluation (PMID: 23613520, 27153395, 31980526, 19405097, 28104920, 25659033). Ten ClinVar submitters have assessed the variant since 2014 and classified as pathogenic/likely pathogenic (n=7) and VUS (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
FANCL-related disorder Uncertain:1
The FANCL c.1022_1024delTAT variant is predicted to result in an in-frame deletion (p.Ile341_Cys342delinsSer). This variant, also known as c.1007_1009del (p.Ile336_Cys337delinsSer), has been reported in the compound heterozygous state in two individuals with Fanconi anemia (Ali et al. 2009. PubMed ID: 19405097; Chandrasekharappa et al. 2013. PubMed ID: 23613520). This variant was also documented in the heterozygous state in individuals with bone marrow failure or a personal history of breast or ovarian cancer (Table S5, Zhang et al. 2015. PubMed ID: 25239263; Tables S4 & S5, Maxwell et al. 2016. PubMed ID: 27153395; Guidugli et al. 2017. PubMed ID: 28104920). Functional studies suggest that this variant alters cellular function (Ali et al. 2009. PubMed ID: 19405097). This variant is listed in ClinVar with varying interpretations ranging from Pathogenic (2), Likely Pathogenic (7), and Uncertain (4) (https://www.ncbi.nlm.nih.gov/clinvar/variation/241247/). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Premature ovarian insufficiency Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at