Submissions for variant NM_000051.4(ATM):c.4049C>T (p.Thr1350Met)

gnomAD frequency: 0.00001  dbSNP: rs587781785

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130040	SCV000184866	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-15	criteria provided, single submitter	clinical testing	The p.T1350M variant (also known as c.4049C>T), located in coding exon 26 of the ATM gene, results from a C to T substitution at nucleotide position 4049. The threonine at codon 1350 is replaced by methionine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Additionally, this variant was identified in 1/167 Italian individuals with cutaneous melanoma who were CDKN2A/ARF- and CDK4-negative and in 0/80 cancer-free controls (Pastorino L et al. Cancers (Basel), 2020 04;12:). This variant was also reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589125	SCV000566662	uncertain significance	not provided	2023-07-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with cutaneous melanoma and high-risk breast cancer, as well as both cases and controls in studies of breast and pancreatic cancer (Kwong et al., 2020; Mizukami et al., 2020; Pastorino et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 30287823, 28119368, 33471991, 32980694, 32068069, 32325837)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543134	SCV000622467	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1350 of the ATM protein (p.Thr1350Met). This variant is present in population databases (rs587781785, gnomAD 0.03%). This missense change has been observed in individual(s) with melanoma, breast and/or ovarian cancer (PMID: 32068069, 32325837, 34262154). ClinVar contains an entry for this variant (Variation ID: 141486). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000130040	SCV000682180	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1350 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cutaneous melanoma (PMID: 32325837). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has also been identified in 13/248774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255215	SCV000694271	uncertain significance	not specified	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4049C>T (p.Thr1350Met) 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 allele was found at a frequency of 5.2e-05 in 271256 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.2e-05 vs 0.004), allowing no conclusion about variant significance. c.4049C>T has been reported in the literature in at least one individual affected with familial cutaneous melanoma (e.g. Pastorino_2020), and in individuals with breast cancer as well as healthy control subjects (Momozawa_2018, Kwong_2020, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 30181556, 32325837, 28119368, 33471991, 32068069). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130040	SCV002528941	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002478391	SCV002789980	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467129	SCV004209539	uncertain significance	Familial cancer of breast	2023-08-29	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000543134	SCV005042616	uncertain significance	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The missense c.4049C>Tp.Thr1350Met variant in ATM gene has been reported previously in heterozygous state in individuals affected with cutaneous melanoma Pastorino et al., 2020. This variant is reported with the allele frequency of 0.005% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance multiple submitters. However, no details are available for independent assessment. The amino acid Thr at position 1350 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr1350Met in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003467129	SCV005919106	uncertain significance	Familial cancer of breast	2024-04-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000543134	SCV001458199	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing