Submissions for variant NM_000135.4(FANCA):c.4249C>G (p.His1417Asp)

gnomAD frequency: 0.00362  dbSNP: rs17227403

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000120955	SCV000257630	uncertain significance	not specified	2015-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226145	SCV000283570	benign	Fanconi anemia	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120955	SCV000594630	benign	not specified	2019-03-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001115284	SCV001273251	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.
GeneDx	RCV001552904	SCV001773678	likely benign	not provided	2020-09-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12444097, 27153395, 9371798, 25525159, 22995991, 24728327)
Sema4, Sema4	RCV000226145	SCV002535047	likely benign	Fanconi anemia	2021-06-25	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001552904	SCV002545836	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FANCA: BP4, BS2; ZNF276: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120955	SCV002765923	benign	not specified	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.4249C>G (p.His1417Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 282888 control chromosomes, including 5 homozygotes (gnomAD). The variant occurs predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4249C>G has been reported in the literature in at least one homozygous individual affected with Fanconi Anemia (Levran_1997). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia. At least one publication reports experimental evidence evaluating the variant's effects on FANCA phosphorylation, interaction with FANCC, FANCF and FANCG and nuclear localization and FANCD2 monoubiquitination. These experiments showed the variant behaved similarly to wild-type (Adachi_2002). Nine ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, two as uncertain significance, two as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120955	SCV002774468	benign	not specified	2021-07-21	criteria provided, single submitter	clinical testing
ITMI	RCV000120955	SCV000085123	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV001115284	SCV001425873	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.	RCV001115284	SCV001458737	benign	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001552904	SCV001798958	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120955	SCV001807600	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001552904	SCV001966075	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915205	SCV004737355	likely benign	FANCA-related disorder	2019-10-31	no assertion criteria provided	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).