Submissions for variant NM_000135.4(FANCA):c.3157C>T (p.Arg1053Cys)

gnomAD frequency: 0.00011  dbSNP: rs376103033

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472481	SCV000547780	likely benign	Fanconi anemia	2025-01-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001509531	SCV001716287	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821268	SCV002066652	uncertain significance	not specified	2020-11-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.3157C>T, in exon 32 that results in an amino acid change, p.Arg1053Cys. This sequence change does not appear to have been previously described in patients with FANCA-related disorders and has been described in the gnomAD database with a low population frequency of 0.087% in the Latino subpopulation (dbSNP rs376103033). The p.Arg1053Cys change affects a poorly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg1053Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Arg1053Cys change remains unknown at this time.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001276510	SCV002495751	uncertain significance	Fanconi anemia complementation group A	2021-04-02	criteria provided, single submitter	clinical testing	FANCA NM_000135.3 exon 32 p.Arg1053Cys (c.3157C>T): This variant has not been reported in the literature but is present in 0.02% (4/15274) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-89749812-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:408205). This variant amino acid Cysteine (Cys) is present in several species including multiple primates and other mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001509531	SCV004222000	uncertain significance	not provided	2024-07-03	criteria provided, single submitter	clinical testing	The FANCA c.3157C>T (p.Arg1053Cys) variant has been reported in the published literature in individuals affected with acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)), head and neck squamous cell carcinoma (HNSCC) (PMID: 28678401 (2017)), and ovarian cancer (PMID: 32546565 (2021)). This variant has also been reported in reportedly healthy individuals (PMID: 32546565 (2021)). The frequency of this variant in the general population, 0.00087 (31/35434 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821268	SCV005205423	uncertain significance	not specified	2024-06-03	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.3157C>T (p.Arg1053Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251440 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (0.00021 vs 0.0022), allowing no conclusion about variant significance. c.3157C>T has been reported in the literature in an individual affected with head and neck squamous cell carcinoma (Chandrasekharappa_2017). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 408205). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001276510	SCV005644736	uncertain significance	Fanconi anemia complementation group A	2024-02-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276510	SCV001462889	uncertain significance	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing