Submissions for variant NM_000135.4(FANCA):c.987_990del (p.His330fs)

dbSNP: rs772359099

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190585	SCV000245609	pathogenic	Fanconi anemia complementation group A	2014-10-07	criteria provided, single submitter	clinical testing	The p.His330AlafsX4 variant in FANCA has been reported in >10 homozygous or compound heterozygous individuals with Fanconi anemia (Levran 1997, Morgan 1999, Najim 2009, De Rocco 2014, FANCA LOVD database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 330 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of FANCA function is an established disease mechanism in fanconia anemia. In summary, this variant meets our criteria to be classified as pathogenic for Fanconi anemia in an autosomal recessive manner (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/) due to the predicted impact to the protein.
GeneDx	RCV000483448	SCV000567944	pathogenic	not provided	2022-03-22	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; This variant is associated with the following publications: (PMID: 21273304, 27041517, 27832981, 28717661, 9371798, 10521298, 28423363, 17924555, 29154021, 24584348, 27535533, 32487094)
Counsyl	RCV000190585	SCV000789247	pathogenic	Fanconi anemia complementation group A	2017-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804476	SCV000944387	pathogenic	Fanconi anemia	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His330Alafs*4) 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 (rs772359099, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with FANCA-related conditions and/or hereditary breast and ovarian cancer and Fanconi anemia (PMID: 9371798, 17924555, 21273304, 27041517, 28423363; Invitae). 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: 208580). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000483448	SCV002068937	pathogenic	not provided	2018-09-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCA gene demonstrated a four base pair deletion in exon 11, c.987_990del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 3 amino acids downstream of the deletion, p.His330Alafs*4. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FANCA protein with potentially abnormal function. This pathogenic sequence change has previously been described in patient with Fanconi anemia (Levran O, et al., 1997; Levran O, et al., 2005; De Rocco D et al., 2014; Pilonetto DV, et al., 2017).
Fulgent Genetics, Fulgent Genetics	RCV000190585	SCV002798338	pathogenic	Fanconi anemia complementation group A	2022-04-17	criteria provided, single submitter	clinical testing
3billion	RCV000190585	SCV003841590	pathogenic	Fanconi anemia complementation group A	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000208580 / PMID: 9371798). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000190585	SCV004195996	pathogenic	Fanconi anemia complementation group A	2023-10-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483448	SCV004218657	pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the FANCA mRNA and causes the premature termination of FANCA protein synthesis. The frequency of this variant in the general population, 0.0003 (6/19952 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with Fanconi anemia and one patient with breast cancer (PMIDs: 29154021 (2018), 28423363 (2017), 28717661 (2017), 24584348 (2014), 21273304 (2011), 17924555 (2008), 10521298 (1999), 9371798 (1997)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000190585	SCV004238184	likely pathogenic	Fanconi anemia complementation group A	2023-03-03	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000190585	SCV001426042	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.
Natera, Inc.	RCV000804476	SCV002095078	pathogenic	Fanconi anemia	2020-08-05	no assertion criteria provided	clinical testing