Submissions for variant NM_020937.4(FANCM):c.869T>C (p.Ile290Thr)

gnomAD frequency: 0.00009  dbSNP: rs377303950

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045549	SCV001209409	uncertain significance	Fanconi anemia	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 290 of the FANCM protein (p.Ile290Thr). This variant is present in population databases (rs377303950, gnomAD 0.008%). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 843021). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
GeneDx	RCV001545299	SCV001764607	uncertain significance	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Observed in individuals with colorectal cancer or head and neck squamous cell carcinoma (PMID: 27713038, 28678401); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27713038, 28678401)
PreventionGenetics, part of Exact Sciences	RCV004536083	SCV004113921	uncertain significance	FANCM-related disorder	2023-03-10	criteria provided, single submitter	clinical testing	The FANCM c.869T>C variant is predicted to result in the amino acid substitution p.Ile290Thr. This variant was reported in an individual with head and neck squamous cell carcinoma (Table S3, Chandrasekharappa et al 2017. PubMed ID: 28678401). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-45618149-T-C). This variant is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/843021/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001545299	SCV004218847	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with head and neck squamous cell carcinoma (PMID: 28678401 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.000077 (10/129082 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.