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

gnomAD frequency: 0.00037  dbSNP: rs540805431

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543810	SCV000626469	likely benign	Fanconi anemia	2025-01-06	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	2025-01-17	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 (PMID: 28678401, 30306255); 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 (PMID: 35495172); 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: 30306255, 35495172, 28678401, 39519399)
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843527	SCV002103107	uncertain significance	Hepatoblastoma		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003942732	SCV004763767	likely benign	FANCD2-related disorder	2023-06-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).