Submissions for variant NM_001018115.3(FANCD2):c.1348A>G (p.Ile450Val)

gnomAD frequency: 0.00016  dbSNP: rs145129959

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552393	SCV000626461	uncertain significance	Fanconi anemia	2022-10-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 456344). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 450 of the FANCD2 protein (p.Ile450Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 28202063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCD2 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	RCV000764453	SCV000895515	uncertain significance	Fanconi anemia complementation group D2	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092962	SCV001249719	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	FANCD2: BP4
Sema4, Sema4	RCV000552393	SCV002529455	uncertain significance	Fanconi anemia	2022-03-11	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488659	SCV004241174	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.1348A>G (p.Ile450Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 152400 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCD2 causing Fanconi Anemia (0.00021 vs 0.00048), allowing no conclusion about variant significance. c.1348A>G has been reported in the literature in individuals affected with breast cancer (Jalkh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28202063). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: three submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001092962	SCV001798584	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001092962	SCV001973627	likely benign	not provided		no assertion criteria provided	clinical testing