Submissions for variant NM_000135.4(FANCA):c.577C>G (p.Leu193Val)

gnomAD frequency: 0.00029  dbSNP: rs141861208

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000660417	SCV000399883	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001753780	SCV000782504	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	BP4
Invitae	RCV000280680	SCV000826812	likely benign	Fanconi anemia	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001753780	SCV001988362	uncertain significance	not provided	2019-12-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28548121, 28259476, 28767289)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000660417	SCV002584751	uncertain significance	Fanconi anemia complementation group A	2023-10-24	criteria provided, single submitter	clinical testing	The FANCA c.577C>G (p.Leu193Val) missense change has a maximum subpopulation frequency of 0.037% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the role of this variant in Fanconi anemia. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753780	SCV004218629	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with pancreatic ductal adenocarcinoma and gastrointestinal stromal tumor (PMIDs: 32659497 (2020) and 28767289 (2017)). The frequency of this variant in the general population, 0.00049 (25/50814 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.	RCV000660417	SCV001459011	uncertain significance	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing