Submissions for variant NM_001018115.3(FANCD2):c.2715+1G>A

gnomAD frequency: 0.00016  dbSNP: rs201811817

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826140	SCV000967667	pathogenic	Fanconi anemia	2016-02-19	criteria provided, single submitter	clinical testing	The c.2715+1G>A variant in FANCD2 has been identified in two individuals with Fa nconi anemia (Kalb 2007) and has also been identified in the general population with the highest frequency found at 0.06% (4/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201 811817). Although this variant is seen in the general population, its frequency is consistent with a recessive carrier frequency. This variant occurs in the inv ariant region (+/- 1,2) of the splice consensus sequence and is predicted to cau se altered splicing leading to an abnormal or absent protein. In addition, in vi tro functional studies provide evidence that the c.2715+1G>A variant causes aber rant splicing (Kalb 2007). In summary, this variant meets our criteria to be cla ssified as pathogenic for Fanconi anemia in an autosomal recessive manner based upon case studies and functional evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000826140	SCV001592098	pathogenic	Fanconi anemia	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 28 of the FANCD2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201811817, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Fanconi anemia (PMID: 17436244, 22720145, 25703294, 28386063). ClinVar contains an entry for this variant (Variation ID: 667394). Studies have shown that disruption of this splice site results in activation of cryptic splice site and introduces a premature termination codon (PMID: 17436244). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001194925	SCV001752590	pathogenic	Fanconi anemia complementation group D2	2021-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001593026	SCV001826338	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with personal and family history of breast cancer (Mantere 2017); This variant is associated with the following publications: (PMID: 28386063, 25703294, 25525159, 28678401, 24448499, 25239263, 17436244, 22829014, 30609409, 30676620, 26689913, 31980526)
Revvity Omics, Revvity	RCV001194925	SCV002023020	pathogenic	Fanconi anemia complementation group D2	2022-03-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001593026	SCV002069135	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCD2 gene demonstrated a sequence change in the canonical splice donor site of intron 28, c.2715+1G>A. This sequence change has previously been described in patients with Fanconi anemia in the compound heterozygous state with another pathogenic variant (PMID: 17436244, PMID: 25703294). This sequence change has also been reported in patients with breast cancer and testicular seminoma in the heterozygous state (PMID: 28386063, PMID: 22829014), however the contribution of this variant to the breast cancer and testicular seminoma is unclear. This sequence change has also been described in gnomAD database with a low frequency of 0.017% in general population and a frequency of 0.048% in Finnish (dbSNP rs201811817). This sequence change is predicted to affect normal splicing of the FANCD2 gene and result in an abnormal protein. These collective evidences indicate that this sequence change is pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000826140	SCV003928638	pathogenic	Fanconi anemia	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.2715+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least two publications reported experimental evidence that this variant affects mRNA splicing and induces the use of a cryptic splice-donor site downstream the exon (Kalb_2007, Mantere_2017). The variant allele was found at a frequency of 0.00017 in 251446 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FANCD2 causing Fanconi Anemia (0.00017 vs 0.00048), allowing no conclusion about variant significance. c.2715+1G>A has been reported in the literature in multiple individuals affected with Fanconi Anemia or Breast Cancer (Kalb_2007, Mantere_2017). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001194925	SCV004196732	pathogenic	Fanconi anemia complementation group D2	2024-03-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001194925	SCV005086471	pathogenic	Fanconi anemia complementation group D2	2023-12-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anaemia, complementation group D2 (MIM#227646). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). Although several publications provided mRNA and protein consequences, limited functional evidence was presented (PMIDs: 17436244, 28386063). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (49 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in individuals with bone marrow failure and/or Fanconi anaemia (ClinVar; PMIDs: 17436244, 25703294). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Leiden Open Variation Database	RCV001194925	SCV001364790	pathogenic	Fanconi anemia complementation group D2	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.