ClinVar Genomic variation as it relates to human health

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); 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; This variant is associated with the following publications: (PMID: 19405097, 27506598, 26822237, 28125075, 26822949, 27659787, 28423363, 28678401, 26296701, 30306255, 32235514, 27153395, 33504652, 34585473, 35929646, 21279724, 36268089, 34308104, 36135330)

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.

FANCL: BS2; VRK2: BS2

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.

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.

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

The FANCL c.1111_1114dupATTA variant is predicted to result in a frameshift and premature protein termination (p.Thr372Asnfs*13). In the literature, this variant is also referred to as c.1095_1908dupAATT (p.Thr367Asnfs*13) and c.1111_1114dup p.(Thr372Asnfs*13).This variant has been reported in the heterozygous state in an individual with esophageal squamous cell carcinoma (ESCC) and a family history of ESCC (Patient P28266, Akbari et al. 2011. PubMed ID: 21279724) and in an individual with ovarian cancer (Patient ID 13-285, Bonache et al. 2018. PubMed ID: 30306255). This variant was also identified in several individuals in a study of variants in Fanconi anemia genes in hereditary cancer patients, however this study considered the cancer risk cancer for monoallelic carriers of this variant to be limited (Supplementary Tables, Del Valle et al. 2020. PubMed ID: 32235514). In a study of individuals with primary ovarian insufficiency, this variant was found in the homozygous and heterozygous states in individuals with no clinical features of Fanconi anemia and this variant was thought to be unlikely causative of the ovarian phenotype in these individuals (Table 3, POI-24 and POI-44, Franca et al. 2020 PubMedID: 33095795). This variant was also reported in a cohort of Fanconi anemia patients and another cohort of hereditary breast and ovarian cancer patients, however this variant was reported to be co-inherited with variants in other genes (Supplementary Tables 3 and 4, Chandrasekharappa et al. 2017. PubMed ID: 28678401; Supplementary Table 3, Tedaldi et al. 2017. PubMed ID: 28423363). This variant is reported in 0.68% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/210988/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.