Submissions for variant NM_001018115.3(FANCD2):c.4281+69G>A

gnomAD frequency: 0.00001  dbSNP: rs754606069

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001820050	SCV002066244	uncertain significance	not specified	2021-08-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCD2 gene demonstrated a sequence change, c.4350G>A, which results in the creation of a premature stop codon at amino acid position 1450, p.Trp1450*. This sequence change occurs in the last exon of the FANCD2 gene and may produce a truncated protein that escapes nonsense mediated decay. This sequence change has been described in the gnomAD database with a frequency of 0.0018% in the non-Finnish European subpopulation (dbSNP rs754606069). This sequence change has previously been described in a individual with pancreatic adenocarcinoma (PMID: 29625052). Due to insufficient evidences and the lack of functional studies, the clinical significance of the c.4350G>A change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820050	SCV002500762	uncertain significance	not specified	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.4350G>A (p.Trp1450X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory. The variant allele was found at a frequency of 8e-06 in 251470 control chromosomes. To our knowledge, no occurrence of c.4350G>A in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Sema4, Sema4	RCV002255650	SCV002529532	uncertain significance	Fanconi anemia	2022-03-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002476628	SCV002797007	uncertain significance	Fanconi anemia complementation group D2	2022-03-07	criteria provided, single submitter	clinical testing
Invitae	RCV002255650	SCV004295750	uncertain significance	Fanconi anemia	2023-07-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1049571). This premature translational stop signal has been observed in individual(s) with pancreatic adenocarcinoma or ovarian cancer (PMID: 29625052, 32546565). This variant is present in population databases (rs754606069, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Trp1450*) in the FANCD2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the FANCD2 protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355853	SCV001550858	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FANCD2 p.W1450* variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in Cosmic, dbSNP (ID: rs754606069) and in control databases in 2 of 251470 chromosomes at a frequency of 0.000007953 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 2 of 113748 chromosomes (freq: 0.000018), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.4350G>A variant leads to a premature stop codon at position 1450, however this occurs in the last exon of the FANCD2 gene and results in less than a 10% protein loss; therefore the potential impact on the protein is unclear. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.