ClinVar Miner

Submissions for variant NM_001018115.3(FANCD2):c.2273G>C (p.Cys758Ser)

gnomAD frequency: 0.00016  dbSNP: rs540805431
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543810 SCV000626469 likely benign Fanconi anemia 2021-12-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV001292722 SCV001481350 uncertain significance Fanconi anemia complementation group D2 2019-07-05 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory,University of Chicago RCV001821496 SCV002070983 uncertain significance not specified 2021-01-04 criteria provided, single submitter clinical testing This sequence change has been previously described in a patient cohort with head and neck squamous cell carcinoma (HNSCC); no other details were provided (PMID: 28678401). This sequence change has been described in the gnomAD database with a relatively higher population frequency of 0.33% in the Latino subpoulation (dbSNP rs540805431). The p.Cys758Ser change affects a highly conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys758Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys758Ser change remains unknown at this time.
Sema4,Sema4 RCV000543810 SCV002529494 uncertain significance Fanconi anemia 2022-03-09 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821496 SCV002555806 likely benign not specified 2022-06-09 criteria provided, single submitter clinical testing Variant summary: FANCD2 c.2273G>C (p.Cys758Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251082 control chromosomes, predominantly at a frequency of 0.0033 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6.82 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2273G>C has been reported in the literature in settings of multigene panel testing for head and neck squamous cell carcinoma (HNSCC) and breast cancer without strong evidence for causality (example Chandrasekharappa_2017, Bonache_2018). To our knowledge no individuals with the variant affected with Fanconi Anemia and no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV002275050 SCV002562387 uncertain significance not provided 2022-07-31 criteria provided, single submitter clinical testing Identified in an individual with head and neck squamous cell carcinoma and in a cohort of probands from families with high breast cancer risk, however, detailed clinical information was not provided (Chandrasekharappa et al., 2017; Bonache et al., 2018); Identified as heterozygous in a patient with hepatoblastoma, multiple congenital anomalies, and developmental delay. Patient also reported to have multiple additional variants in known/candidate cancer predisposition genes (Aguiar et al., 2022).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28678401, 30306255, 35495172)
Molecular Oncology - Human Genetics Lab,University of Sao Paulo RCV001843527 SCV002103107 uncertain significance Hepatoblastoma no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.