Submissions for variant NM_000051.4(ATM):c.4358T>C (p.Ile1453Thr)

dbSNP: rs587782126

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482060	SCV000572123	uncertain significance	not provided	2024-08-23	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054691	SCV001219039	uncertain significance	Ataxia-telangiectasia syndrome	2023-08-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 422614). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1453 of the ATM protein (p.Ile1453Thr). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193631	SCV001362599	uncertain significance	not specified	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4358T>C (p.Ile1453Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276944 control chromosomes (gnomAD). 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.4358T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000482060	SCV002497174	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329157	SCV002627514	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	The p.I1453T variant (also known as c.4358T>C), located in coding exon 28 of the ATM gene, results from a T to C substitution at nucleotide position 4358. The isoleucine at codon 1453 is replaced by threonine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003470580	SCV004209488	uncertain significance	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003470580	SCV005038983	uncertain significance	Familial cancer of breast	2024-05-02	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 1453 of the ATM protein (p.Ile1453Thr).his amino acid position is well conserved (PhyloP=7.75) . This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 422614). In addition, the in silico prediction for this alteration is inconclusive. 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.
Natera, Inc.	RCV001054691	SCV002082415	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-23	no assertion criteria provided	clinical testing