Submissions for variant NM_001018115.3(FANCD2):c.1777C>T (p.Pro593Ser)

gnomAD frequency: 0.00071  dbSNP: rs147523071

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459559	SCV000547226	uncertain significance	Fanconi anemia	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 593 of the FANCD2 protein (p.Pro593Ser). This variant is present in population databases (rs147523071, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 33558524). 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, which suggests that this missense change does not adversely affect protein function. 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	2022-09-29	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in association with Fanconi anemia but is present in the Genome Aggregation Database (Highest reported MAF: 0.1% (184/129068); http://gnomad.broadinstitute.org/variant/3-10103845-C-T). This variant is also present in ClinVar (Variation ID:134313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, 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.
Baylor Genetics	RCV000764454	SCV001481375	uncertain significance	Fanconi anemia complementation group D2	2019-10-22	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001541664	SCV001759689	uncertain significance	not provided	2021-01-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a head and neck squamous cell carcinoma in the literature (Chandrasekharappa et al., 2017); This variant is associated with the following publications: (PMID: 28678401, 24728327, 27626691)
Genetic Services Laboratory, University of Chicago	RCV000120987	SCV002070980	uncertain significance	not specified	2018-03-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000459559	SCV002529472	likely benign	Fanconi anemia	2021-04-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001541664	SCV003916404	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	FANCD2: BP4, BP5
PreventionGenetics, part of Exact Sciences	RCV003415914	SCV004115959	uncertain significance	FANCD2-related disorder	2022-12-27	criteria provided, single submitter	clinical testing	The FANCD2 c.1777C>T variant is predicted to result in the amino acid substitution p.Pro593Ser. This variant has been reported in an individual with unilateral breast cancer (Moradian et al. 2021. PubMed ID: 33558524) and in an individual with head and neck squamous cell carcinoma (Table S3 - Chandrasekharappa et al. 2017. PubMed ID: 28678401). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is higher than expected for a pathogenic variant (http://gnomad.broadinstitute.org/variant/3-10103845-C-T) and in ClinVar this variant has conflicting interpretations of pathogenicity of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/134313/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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	Malignant tumor of breast	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001541664	SCV001799087	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001541664	SCV001974216	likely benign	not provided		no assertion criteria provided	clinical testing