Submissions for variant NM_001018115.3(FANCD2):c.3446C>T (p.Ala1149Val)

gnomAD frequency: 0.00063  dbSNP: rs147675860

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094805	SCV000439600	benign	Fanconi anemia complementation group D2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000299211	SCV000558535	benign	Fanconi anemia	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514928	SCV000610965	likely benign	not provided	2017-08-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514928	SCV005041626	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	FANCD2: BP4, BS1, BS2
ITMI	RCV000120998	SCV000085166	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120998	SCV001548716	benign	not specified		no assertion criteria provided	clinical testing	The FANCD2 p.Ala1149Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs147675860), ClinVar (classified as a VUS by Illumina for Fanconi Anemia, likely benign by Center for Pediatric Genomic Medicine at Children's Mercy Hospital and Clinics and benign by Invitae for Fanconi Anemia) and Cosmic (FATHMM prediction: neutral; score=0.19). The variant was identified in control databases in 352 of 281318 chromosomes (5 homozygous) at a frequency of 0.001251 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 320 of 19928 chromosomes (freq: 0.01606), African in 22 of 24706 chromosomes (freq: 0.000891), Other in 2 of 7158 chromosomes (freq: 0.000279), Latino in 2 of 35354 chromosomes (freq: 0.000057), European (non-Finnish) in 5 of 128722 chromosomes (freq: 0.000039) and South Asian in 1 of 30612 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Ala1149 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 this variant meets our laboratory's criteria to be classified as benign.