Submissions for variant NM_000051.4(ATM):c.6758A>C (p.Lys2253Thr)

dbSNP: rs786203332

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166597	SCV000217401	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	clinical testing	The p.K2253T variant (also known as c.6758A>C), located in coding exon 45 of the ATM gene, results from an A to C substitution at nucleotide position 6758. The lysine at codon 2253 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231110	SCV000283025	uncertain significance	Ataxia-telangiectasia syndrome	2022-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 2253 of the ATM protein (p.Lys2253Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic lymphocytic leukemia (PMID: 28652578). ClinVar contains an entry for this variant (Variation ID: 186930). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166597	SCV000904718	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174902	SCV001338330	uncertain significance	not specified	2020-02-25	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6758A>C (p.Lys2253Thr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6758A>C has been reported in the literature in an individual affected with CLL (Tiao_2017). This report does not provide unequivocal conclusions about the association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003468788	SCV004210322	uncertain significance	Familial cancer of breast	2023-06-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000231110	SCV002077412	uncertain significance	Ataxia-telangiectasia syndrome	2020-10-12	no assertion criteria provided	clinical testing