Submissions for variant NM_000135.4(FANCA):c.3558dup (p.Arg1187fs)

dbSNP: rs747851434

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000003613	SCV000486649	pathogenic	Fanconi anemia complementation group A	2016-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630905	SCV000751878	pathogenic	Fanconi anemia	2024-09-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1187Glufs*28) in the FANCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is present in population databases (rs747851434, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 9399890, 17924555, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3444). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001818121	SCV002072231	pathogenic	not provided	2021-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001818121	SCV002504446	pathogenic	not provided	2022-04-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 3444; ClinVar); This variant is associated with the following publications: (PMID: 10431244, 17924555, 9399890, 31589614, 33718801, 24584348)
PreventionGenetics, part of Exact Sciences	RCV003398432	SCV004119271	pathogenic	FANCA-related disorder	2023-09-15	criteria provided, single submitter	clinical testing	The FANCA c.3558dupG variant is predicted to result in a frameshift and premature protein termination (p.Arg1187Glufs*28). In the literature this variant is also referred to as c.3559insG and c.3558_3559insG. This variant has been reported in the homozygous and presumed compound heterozygous states in individuals with Fanconi anemia (Savino et al. 1997. PubMed ID: 9399890; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89811434-T-TC). Frameshift variants in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000003613	SCV004196554	pathogenic	Fanconi anemia complementation group A	2024-03-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003613	SCV005642615	pathogenic	Fanconi anemia complementation group A	2024-02-22	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV005394110	SCV006052437	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-16	criteria provided, single submitter	clinical testing	PVS1, PM3 Actualización DA (17/02/2025): PVS1 (8) + PM3 (2) -> PAT (10). The c.3558dup pathogenic mutation, located at coding exon 36 of 43 exons in the FANCA gene, results from a duplication of one nucleotide at nucleotide position 3558, causing a translational frameshift with a predicted alternate stop codon (p.(Arg1187Glufs*28)). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (PVS1). This variant is found in 6/264120 alleles, at a frequency of 0.0022% in the gnomAD v2.1.1 database, non-cancer dataset. Computational tools predict no significant impact on splicing. This variant has been identified in at least six individuals affected with Fanconi anemia (PMID 9399890, 17924555). It has been reported in at least one Fanconi anemia proband in homozygosis (PMID 9399890) (PM3). The variant was also identified in the following databases, ClinVar** (9x as pathogenic), LOVD (21x as pathogenic, 2 as uncertain significance). Based on the available evidence to date, this variant is classified as pathogenic (PVS1, PM3) according ACMG guidelines.
OMIM	RCV000003613	SCV000023771	pathogenic	Fanconi anemia complementation group A	1999-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003613	SCV001458758	pathogenic	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing