Submissions for variant NM_000135.4(FANCA):c.1874G>C (p.Cys625Ser)

gnomAD frequency: 0.00230  dbSNP: rs139235751

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255908	SCV000321624	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	The C625S variant in the FANCA gene has been previously reported in an individual with Fanconi anemia who also harbored a multi-exon FANCA deletion; however, the phase of these two variants was not confirmed, as parental testing was not performed (Castella et al., 2011). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports C625S was observed in 27/8600 (0.31%) alleles from individuals of European background, indicating it may be a rare variant in this population. The C625S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C625S as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000255908	SCV000343524	likely benign	not specified	2016-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000475267	SCV000558869	benign	Fanconi anemia	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255908	SCV000594639	uncertain significance	not specified	2016-11-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255908	SCV000603559	uncertain significance	not specified	2017-04-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000989672	SCV001140204	uncertain significance	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000989672	SCV001278635	uncertain significance	Fanconi anemia complementation group A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000989672	SCV001652749	uncertain significance	Fanconi anemia complementation group A	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001800637	SCV002010571	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255908	SCV002047065	benign	not specified	2021-05-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000475267	SCV002534929	likely benign	Fanconi anemia	2022-01-21	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV001800637	SCV002541386	uncertain significance	not provided	2021-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000255908	SCV002556224	benign	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.1874G>C (p.Cys625Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1612748 control chromosomes, predominantly at a frequency of 0.0031 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 equal to the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022) and the variant was found in 8 homozygotes, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1874G>C has been reported in the literature in at least two individuals affected with Fanconi Anemia, however in one case it was not considered to be pathogenic as it was reportedly located in cis downstream from a pathogenic variant and was also observed at a similar frequency in healthy controls (Castella_2011, De Rocco_2014). 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: 21273304, 24584348, 34864095). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Ten submitters have classified the variant as uncertain significance, six submitters classified it as benign/likely benign, and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000989672	SCV002584661	uncertain significance	Fanconi anemia complementation group A	2023-07-11	criteria provided, single submitter	clinical testing	The FANCA c.1874G>C (p.Cys625Ser) missense change has a maximum subpopulation frequency of 0.39% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Fanconi anemia who also harbored a deletion of exons 18-20 in FANCA, however the phase of the two variants was not known (PMID: 21273304). 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.
Revvity Omics, Revvity	RCV000989672	SCV003833892	uncertain significance	Fanconi anemia complementation group A	2022-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001800637	SCV004143610	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	FANCA: BS2
PreventionGenetics, part of Exact Sciences	RCV003920022	SCV004736568	likely benign	FANCA-related condition	2022-02-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Leiden Open Variation Database	RCV000989672	SCV001425811	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000989672	SCV001462951	benign	Fanconi anemia complementation group A	2020-05-08	no assertion criteria provided	clinical testing