Submissions for variant NM_000135.4(FANCA):c.377C>T (p.Thr126Met)

dbSNP: rs139160837

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464585	SCV000547782	likely benign	Fanconi anemia	2025-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV002264943	SCV002546902	uncertain significance	not provided	2022-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002264943	SCV002774567	uncertain significance	not provided	2024-10-07	criteria provided, single submitter	clinical testing	The FANCA c.377C>T (p.Thr126Met) variant has been reported in the published literature in an individual with pancreatic adenocarcinoma (PMID: 39256447 (2024)). The frequency of this variant in the general population, 0.00088 (22/24940 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Ambry Genetics	RCV002526413	SCV003698122	uncertain significance	Inborn genetic diseases	2021-11-22	criteria provided, single submitter	clinical testing	The c.377C>T (p.T126M) alteration is located in exon 4 (coding exon 4) of the FANCA gene. This alteration results from a C to T substitution at nucleotide position 377, causing the threonine (T) at amino acid position 126 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV001276567	SCV004048465	uncertain significance	Fanconi anemia complementation group A		criteria provided, single submitter	clinical testing	The missense variant p.Thr126Met in FANCA (NM_000235.4) has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Thr126Met variant is novel (not in any individuals) in 1000 Genomes. The amino acid Thr at position 126 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is variable across species. For these reasons, this variant has been classified as Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001276567	SCV005402117	uncertain significance	Fanconi anemia complementation group A	2024-04-04	criteria provided, single submitter	clinical testing	The FANCA c.377C>T (p.Thr126Met) missense change has a maximum subpopulation frequency of 0.088% 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 clinical significance of this variant. It has therefore been classified as of uncertain significance.
Natera, Inc.	RCV001276567	SCV001462965	uncertain significance	Fanconi anemia complementation group A	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902647	SCV004723900	uncertain significance	FANCA-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The FANCA c.377C>T variant is predicted to result in the amino acid substitution p.Thr126Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.088% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408207/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.