Submissions for variant NM_000135.4(FANCA):c.709+5G>A

gnomAD frequency: 0.00001  dbSNP: rs759877008

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474895	SCV000547740	pathogenic	Fanconi anemia	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the FANCA gene. It does not directly change the encoded amino acid sequence of the FANCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 10 novel amino acids amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs759877008, gnomAD 0.02%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 8896563, 10094191, 19423727, 21273304). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 740+5G>A or IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 408169). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FANCA function (PMID: 19423727). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 19423727). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000673202	SCV000798378	likely pathogenic	Fanconi anemia complementation group A	2018-03-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000673202	SCV001429202	pathogenic	Fanconi anemia complementation group A	2020-01-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000673202	SCV002022293	pathogenic	Fanconi anemia complementation group A	2021-05-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821265	SCV002065905	likely pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCA gene demonstrated a sequence change located near the canonical splice donor site in intron 7, c.709+5G>A. This sequence change has been described in the gnomAD database with a frequency of 0.02% in the East Asian subpopulation (dbSNP rs759877008). This sequence change has been previously described, along with other pathogenic variants, in the individuals with Fanconi anemia (PMID: 21273304, 8896563, 19423727, 10094191) and in the heterozygous state in an individual with a personal history of ovarian cancer and family history of Lynch syndrome related cancers (PMID: 32235514). Based on in-silico splice prediction programs, this sequence change likely affects normal splicing of the FANCA gene and an experimental study demonstrated that this sequence change impacts normal splicing leading to the production of an abnormal protein with impaired function (PMID: 19423727). Based on these collective evidences, this sequence change is classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000673202	SCV002761920	pathogenic	Fanconi anemia complementation group A	2020-05-01	criteria provided, single submitter	clinical testing	The FANCA:c.709+5G>A variant is a single base change located in intron 7. The variant has been reported in the literature in individuals with a second pathogenic FANCA variant and is associated with disease (PMID: 21273304, PMID: 29098742) (PS1). RNA studies demonstrate that the variant results in aberrant splicing and the insertion of 30bp intronic sequence. The insertion adds 10 amino acids in-frame between codons 236 and 237 (PMID: 8896563). Functional studies show that the variant is unable to restore FANCD2 monoubiquitination in FANCA-deficient lymphoblasts supporting its pathogenicity (PMID: 19423727) (PS3). The variant is rare in population databases at 0.002% (5 het/ 279588 allele count) (PP). It is described in ClinVar as pathogenic/ likely pathogenic and HGMD (2020.1) as disease causing (PP5). Splice prediction programs in Alamut also predict the variant will remove the exon 7 donor site.
Fulgent Genetics, Fulgent Genetics	RCV000673202	SCV002796743	pathogenic	Fanconi anemia complementation group A	2022-05-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000673202	SCV004196024	pathogenic	Fanconi anemia complementation group A	2024-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001821265	SCV004218640	pathogenic	not provided	2022-10-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (4/19948 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been detected in individuals with Fanconi Anemia. Those individuals were compound heterozygous for the variant and a pathogenic variant in the FANCA gene (PMID: 17924555 (2008), 19423727 (2009), 21273304 (2011), 29098742 (2018)) . It has been reported in an individual with ovarian cancer (PMID: 32235514 (2020)). A functional study has demonstrated that this variant has a deleterious effect on FANCA protein function (PMID: 19423727 (2009)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper FANCA mRNA splicing . Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000673202	SCV000224033	pathogenic	Fanconi anemia complementation group A	2009-07-02	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000673202	SCV001425625	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Johan den Dunnen.
Natera, Inc.	RCV000673202	SCV001459006	pathogenic	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing