Submissions for variant NM_001197104.2(KMT2A):c.6793A>C (p.Thr2265Pro)

gnomAD frequency: 0.00002  dbSNP: rs782707495

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002854056	SCV003616891	likely benign	Inborn genetic diseases	2022-05-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003730290	SCV004536271	uncertain significance	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2265 of the KMT2A protein (p.Thr2265Pro). This variant is present in population databases (rs782707495, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with KMT2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2289986). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KMT2A protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005406622	SCV006071487	uncertain significance	not specified	2025-03-24	criteria provided, single submitter	clinical testing	Variant summary: KMT2A c.6793A>C (p.Thr2265Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250940 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6793A>C in individuals affected with Wiedemann-Steiner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2289986). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003906592	SCV004735629	likely benign	KMT2A-related disorder	2023-09-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).