Submissions for variant NM_021922.3(FANCE):c.2T>C (p.Met1Thr)

dbSNP: rs1462766132

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370136	SCV001566601	uncertain significance	Fanconi anemia complementation group E	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FANCE mRNA. The next in-frame methionine is located at codon 99. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of FANCE-related conditions (PMID: 33084842). ClinVar contains an entry for this variant (Variation ID: 1060674). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003120585	SCV003801167	likely pathogenic	Fanconi anemia	2023-01-04	criteria provided, single submitter	clinical testing	Variant summary: FANCE 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. One of two in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 53280 control chromosomes. Alternatively, N-terminal truncation or extension of the encoded protein can also occur due to translation initiation at an alternative initiation codon. The next downstream in-frame initiation codon is at Met 99. Activation of the potential downstream translation initiation site would result in a shortened protein missing the first 98 amino acids from the protein sequence. Other pathogenic variants have been reported upstream of this alternate codon (e.g. p.Gln31Ter, p.Arg89Ter; ClinVar and HGMD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.