Submissions for variant NM_000135.4(FANCA):c.3950G>A (p.Arg1317Gln)

gnomAD frequency: 0.00006  dbSNP: rs376523966

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094402	SCV000399813	uncertain significance	Fanconi anemia complementation group A	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.
Invitae	RCV000368836	SCV000626199	likely benign	Fanconi anemia	2023-11-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820952	SCV002071384	uncertain significance	not specified	2021-09-14	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with FANCA-related disorders. This sequence change has been described in the gnomAD database with a low population frequency of 0.0037% (dbSNP rs376523966). The p.Arg1317Gln change affects a poorly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg1317Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to this insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg1317Gln change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV001094402	SCV002812108	uncertain significance	Fanconi anemia complementation group A	2022-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477891	SCV004218592	uncertain significance	not provided	2022-09-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00013 (3/22790 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with pancreatic neuroendocrine tumors (PMID: 28767289 (2017)), epithelial ovarian cancer (EOC) (PMID: 32546565 (2021)), and healthy, unaffected individuals (PMID: 32546565 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV001094402	SCV001458745	uncertain significance	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing