Submissions for variant NM_018062.4(FANCL):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00001  dbSNP: rs761291501

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686799	SCV000814334	pathogenic	Fanconi anemia	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FANCL mRNA. The next in-frame methionine is located at codon 74. This variant is present in population databases (rs761291501, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with breast cancer, clinical features of Fanconi anemia, and/or glioma (PMID: 29335925, 29625052, 31300551, 33727708, 34008892; Invitae). ClinVar contains an entry for this variant (Variation ID: 566870). This variant disrupts the E2-like fold (ELF) domain of the FANCL protein, which is required for its interaction with the FANCB-FAAP100 complex as well as for non-covalent binding to ubiquitin (PMID: 26149689, 27986371). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090968	SCV001246768	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	FANCL: PVS1, PM2
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729683	SCV001976706	pathogenic	Fanconi anemia complementation group L	2021-10-01	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Genetic Services Laboratory, University of Chicago	RCV001816699	SCV002065831	uncertain significance	not specified	2021-05-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCL gene demonstrated a sequence change, c.2T>C, in exon 1 that results in the loss of the initiator codon, methionine, in the FANCL mRNA. This sequence change has been described in the gnomAD database with a frequency of 0.011% in the European (non-Finnish) subpopulation. This variant has been reported in an individual with male breast cancer diagnosed at a young age who also had a family history of breast cancer (PMID: 29335925). Although experimental studies are not available for this variant, the next in-frame methionine in the NM_ 018062.3 transcript is located at codon 74 in exon 4. No clearly pathogenic variants have been described upstream of the methionine residue at codon 74 to date. Due to the lack of sufficient evidences and functional studies, the clinical significance of the FANCL c.2T>C remains unknown at this time.
Neuberg Centre For Genomic Medicine, NCGM	RCV001729683	SCV002072933	pathogenic	Fanconi anemia complementation group L		criteria provided, single submitter	clinical testing	The initiator codon variant p.M1T in FANCL (NM_018062.4) has been reported previously in males with breast cancer (Fostira F et al). The variant has been submitted to ClinVar as Pathogenic. The p.M1T variant is observed in 12/1,13,460 (0.0106%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.M1T variant is a start loss variant and no nearby start loss variant is present and hence it is predicted to damaging. Other variants affecting the same residue have been previously reported to be disease causing (Miles JA et al). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000686799	SCV004021150	likely pathogenic	Fanconi anemia	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: FANCL c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is located at codon 74 in exon 4. Four other variants affecting the same initiation codon have been scored as likely pathogenic in ClinVar, providing evidence for the critical nature of this codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCL causing Fanconi Anemia (4.8e-05 vs 0.00028), allowing no conclusion about variant significance. c.2T>C has been reported in the literature in homozygous individuals affected with Fanconi Anemia (examples: Marinakis_2021, Spedicati_2021) as well as in individuals affected with various cancers (male breast cancer, colorectal cancer, low-grade glioma, uterine carcinoma) or polyposis syndrome without evidence of causality (examples: Fostira_2018, Huang_2018, Staninova-Stojovska_2019, Chirita-Emandi_2020, Ciccarrone_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31937788, 35454841, 29335925, 29625052, 34008892, 33727708, 31942411). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=3), likely pathogenic (n=1), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Leiden Open Variation Database	RCV001090968	SCV001365347	pathogenic	not provided	2019-12-23	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira.