Submissions for variant NM_001018115.3(FANCD2):c.1265C>G (p.Ser422Cys)

gnomAD frequency: 0.00004  dbSNP: rs765378218

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312593	SCV000439474	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366047	SCV001562335	uncertain significance	Fanconi anemia	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 422 of the FANCD2 protein (p.Ser422Cys). 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 variant has not been reported in the literature in individuals affected with FANCD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 342265). 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 with a negative predictive value of 80%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000312593	SCV002495755	uncertain significance	Fanconi anemia complementation group D2	2021-03-30	criteria provided, single submitter	clinical testing	FANCD2 NM_033084.4 exon 15 p.Ser422Cys (c.1265C>G): This variant has not been reported in the literature but is present in 0.01% (2/15288) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-10046710-C-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:342265). This variant amino acid Cysteine (Cys) is present in >10 species including multiple mammals and 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.
Fulgent Genetics, Fulgent Genetics	RCV000312593	SCV002781037	uncertain significance	Fanconi anemia complementation group D2	2024-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV004721338	SCV005327698	uncertain significance	not provided	2024-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge