Submissions for variant NM_002382.5(MAX):c.56A>T (p.Gln19Leu)

gnomAD frequency: 0.00004  dbSNP: rs200547781

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473057	SCV000541537	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 19 of the MAX protein (p.Gln19Leu). This variant is present in population databases (rs200547781, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MAX-related conditions. ClinVar contains an entry for this variant (Variation ID: 404106). 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.
Ambry Genetics	RCV000562291	SCV000673597	likely benign	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001111570	SCV001269138	likely benign	Pheochromocytoma	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Sema4, Sema4	RCV000562291	SCV002535917	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	curation
GeneDx	RCV002284390	SCV002574644	uncertain significance	not provided	2022-05-26	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	RCV002480339	SCV002773899	benign	not specified	2021-08-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424008	SCV004117991	uncertain significance	MAX-related condition	2023-01-19	criteria provided, single submitter	clinical testing	The MAX c.56A>T variant is predicted to result in the amino acid substitution p.Gln19Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.21% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-65568271-T-A). It is interpreted as uncertain in ClinVar by the vast majority of clinical submitters (https://preview.ncbi.nlm.nih.gov/clinvar/variation/404106/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV001111570	SCV004191932	uncertain significance	Pheochromocytoma	2023-10-06	criteria provided, single submitter	clinical testing