Submissions for variant NM_033084.5(FANCD2):c.1777C>T (p.Pro593Ser) (rs147523071)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459559	SCV000547226	uncertain significance	Fanconi anemia	2019-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 593 of the FANCD2 protein (p.Pro593Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs147523071, ExAC 0.1%). This variant has not been reported in the literature in individuals with FANCD2-related disease. ClinVar contains an entry for this variant (Variation ID: 134313). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics	RCV000764454	SCV000895516	uncertain significance	Fanconi anemia, complementation group D2	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764454	SCV000898676	uncertain significance	Fanconi anemia, complementation group D2	2018-11-07	criteria provided, single submitter	clinical testing	FANCD2 NM_033084.4 exon 20 p.Pro593Ser (c.1777C>T): This variant has not been reported in the literature and is present in 0.1% (184/129068) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-10103845-C-T). This variant is present in ClinVar (Variation ID:134313). This variant amino acid Serine (Ser) is present in several species including multiple primates and other mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina	RCV000764454	SCV001306118	uncertain significance	Fanconi anemia, complementation group D2	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ITMI	RCV000120987	SCV000085155	not provided	not specified	2013-09-19	no assertion provided	reference population
Center of Medical Genetics and Primary Health Care	RCV001004843	SCV000987266	uncertain significance	breast cancer	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000883 > 0.000584 derived from the 206 clinically reported variants in gene FANCD2 of which 16 PATH, 103 VUS and 87 BEN. BP1 Benign Supporting: 32 out of 35 non-VUS missense variants in gene FANCD2 are BEN = 91.4% > threshold of 51.0%, and 87 out of 206 clinically reported variants in gene FANCD2 are BEN = 42.2% > threshold of 24.0%. BP4 Benign Supporting: 13 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL, SIFT, PolyPhen-2 and Align-GVGD vs no pathogenic predictions and the position is not conserved. 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.