Submissions for variant NM_000135.4(FANCA):c.1675G>A (p.Glu559Lys)

gnomAD frequency: 0.00004  dbSNP: rs201323171

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094255	SCV000399859	uncertain significance	Fanconi anemia complementation group A	2018-01-12	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.
Invitae	RCV000384108	SCV000931952	uncertain significance	Fanconi anemia	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 559 of the FANCA protein (p.Glu559Lys). This variant is present in population databases (rs201323171, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 321356). 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 expected to disrupt FANCA 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.
Sema4, Sema4	RCV000384108	SCV002534921	uncertain significance	Fanconi anemia	2021-04-14	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001094255	SCV002791869	uncertain significance	Fanconi anemia complementation group A	2021-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522901	SCV003600921	uncertain significance	Inborn genetic diseases	2021-12-14	criteria provided, single submitter	clinical testing	The c.1675G>A (p.E559K) alteration is located in exon 18 (coding exon 18) of the FANCA gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the glutamic acid (E) at amino acid position 559 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003972373	SCV004798155	uncertain significance	FANCA-related condition	2023-12-02	criteria provided, single submitter	clinical testing	The FANCA c.1675G>A variant is predicted to result in the amino acid substitution p.Glu559Lys. This variant was reported in an individual with pancreatic cancer (eTable 4 in Yin et al. 2022. PubMed ID: 35171259). This variant is reported in 0.054% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000384108	SCV002095017	uncertain significance	Fanconi anemia	2019-10-28	no assertion criteria provided	clinical testing