Submissions for variant NM_022725.4(FANCF):c.241G>T (p.Ala81Ser)

gnomAD frequency: 0.00048  dbSNP: rs145057187

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225823	SCV000290668	uncertain significance	Fanconi anemia	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 81 of the FANCF protein (p.Ala81Ser). This variant is present in population databases (rs145057187, gnomAD 0.2%). This missense change has been observed in individual(s) with bone marrow failure and shortened telomeres (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 241437). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV000764969	SCV000370176	uncertain significance	Fanconi anemia complementation group F	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.
Fulgent Genetics, Fulgent Genetics	RCV000764969	SCV000896146	uncertain significance	Fanconi anemia complementation group F	2022-04-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820762	SCV002071473	uncertain significance	not specified	2020-03-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCF gene demonstrated a sequence change, c.241G>T, in exon 1 that results in an amino acid change, p.Ala81Ser. This sequence change has been described in the gnomAD database with a frequency of 0.21% in the Ashkenazi Jewish sub-population (dbSNP rs145057187). The p.Ala81Ser change has been identified in one individual with bone marrow failure (PMID: 30995915). The p.Ala81Ser change affects a poorly conserved amino acid residue located in a domain of the FANCF protein that is not known to be functional. The p.Ala81Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala81Ser change remains unknown at this time.
Sema4, Sema4	RCV000225823	SCV002530480	uncertain significance	Fanconi anemia	2022-02-11	criteria provided, single submitter	curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764969	SCV003919932	uncertain significance	Fanconi anemia complementation group F	2022-12-21	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 1 individual with bone marrow failure (Arias-Salgado 2019 PMID: 30995915). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.2% [22/10350], including 1 homozygote; https://gnomad.broadinstitute.org/variant/11-22647116-C-A?dataset=gnomad_r2_1), and in ClinVar (Variation ID: 241437). Evolutionary conservation and computational prediction tools strongly suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mendelics	RCV003492014	SCV004232580	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884425	SCV004698745	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	FANCF: BP4, BS1