Submissions for variant NM_000135.4(FANCA):c.26C>T (p.Ser9Phe)

dbSNP: rs752776388

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247242	SCV001420651	uncertain significance	Fanconi anemia	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 9 of the FANCA protein (p.Ser9Phe). 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 FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 971458). 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 FANCA protein function with a negative predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences	RCV003426014	SCV004118608	uncertain significance	FANCA-related disorder	2023-08-18	criteria provided, single submitter	clinical testing	The FANCA c.26C>T variant is predicted to result in the amino acid substitution p.Ser9Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89882998-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV005340729	SCV006002072	uncertain significance	Inborn genetic diseases	2024-12-15	criteria provided, single submitter	clinical testing	The p.S9F variant (also known as c.26C>T), located in coding exon 1 of the FANCA gene, results from a C to T substitution at nucleotide position 26. The serine at codon 9 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Natera, Inc.	RCV001247242	SCV002093164	uncertain significance	Fanconi anemia	2021-09-01	no assertion criteria provided	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV003387442	SCV004098870	uncertain significance	Fanconi anemia complementation group A	2020-10-16	no assertion criteria provided	clinical testing	The p.Ser9Phe variant in the FANCA gene has not been previously reported in association with disease. This variant has been identified in 2/122,936 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Of note, this position has a low coverage warning in gnomAD and allele frequencies may not be accurate. Computational tools predict that the p.Ser9Phe variant does not impact protein function; however, the accuracy of in silico algorithms is limited. The serine at position 9 is poorly evolutionarily conserved and 1 species (platypus)/100 vertebrate species has a phenylalanine at this position. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ser9Phe variant is uncertain. Additional information is needed to resolve the significance of this variant [ACMG evidence codes used: PM2; BP4]