Submissions for variant NM_000051.4(ATM):c.6952A>C (p.Lys2318Gln)

dbSNP: rs1449259481

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566540	SCV000665682	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-19	criteria provided, single submitter	clinical testing	The p.K2318Q variant (also known as c.6952A>C), located in coding exon 46 of the ATM gene, results from an A to C substitution at nucleotide position 6952. The lysine at codon 2318 is replaced by glutamine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566540	SCV000687740	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818244	SCV000958845	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2318 of the ATM protein (p.Lys2318Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823, 35218119). ClinVar contains an entry for this variant (Variation ID: 481352). 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 ATM 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030601	SCV001193486	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192419	SCV001360531	uncertain significance	not specified	2021-03-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6952A>C (p.Lys2318Gln) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6952A>C has been reported in the literature as a VUS in Japanese individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer as the variant was identified in cases and in controls with OR and 95% CI not supportive of a pathogenic outcome (Momozawa_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
GeneDx	RCV001770510	SCV001994661	uncertain significance	not provided	2019-06-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30287823)
Sema4, Sema4	RCV000566540	SCV002536753	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Natera, Inc.	RCV000818244	SCV002079997	uncertain significance	Ataxia-telangiectasia syndrome	2021-07-15	no assertion criteria provided	clinical testing