Submissions for variant NM_000051.4(ATM):c.133C>T (p.Arg45Trp)

gnomAD frequency: 0.00009  dbSNP: rs3218684

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129025	SCV000172930	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	The p.R45W variant (also known as c.133C>T), located in coding exon 2 of the ATM gene, results from a C to T substitution at nucleotide position 133. The arginine at codon 45 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Finnish breast cancer cohort; however, authors classified p.R45W as a polymorphism due to its location outside of known ATM functional domains (Allinen M et al. J. Med. Genet. 2002 Mar;39:192-6). This alteration was also reported in an unaffected individual (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). In addition, this alteration has been reported in a kidney renal clear cell carcinoma patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat. Commun. 2015 Dec 22;6:10086), and in a breast cancer patient with high risk family history (Tung N et al. Cancer 2015 Jan;121(1):25-33). 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	RCV000199094	SCV000254058	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 45 of the ATM protein (p.Arg45Trp). This variant is present in population databases (rs3218684, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or renal cancer (PMID: 11897822, 25186627, 26689913). ClinVar contains an entry for this variant (Variation ID: 140832). 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 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.
GeneDx	RCV000219679	SCV000278808	uncertain significance	not provided	2024-02-28	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 a personal history of breast or kidney cancer, as well as in unaffected controls (PMID: 35402282, 11897822, 25186627, 19781682, 28652578, 29684080, 26689913, 28779002, 33471991); This variant is associated with the following publications: (PMID: 19781682, 35402282, 11897822, 26689913, 28652578, 29684080, 28779002, 25186627, 33471991, 34262154, 38136308)
Color Diagnostics, LLC DBA Color Health	RCV000129025	SCV000681970	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 45 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 individuals affected breast cancer (PMID: 11897822, 25186627, 28779002, 33471991) but also in unaffected control individuals (PMID: 19781682, 28779002, 33471991). This variant has been identified in 7/251182 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	RCV001199867	SCV001370605	uncertain significance	not specified	2022-04-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.133C>T (p.Arg45Trp) results in a non-conservative amino acid change located in the Telomere length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251182 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.133C>T has been reported in the literature in individuals affected with breast cancer (example, Allinen_2002, Tung_2015). It has also been reported as a rare germline variant in the TGCA (The Cancer Genome Atlas) cohort (Lu_2015) and in control individuals (example, Tavtigian_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or with breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Sema4, Sema4	RCV000129025	SCV002530298	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498640	SCV002806947	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-02-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315869	SCV004018634	likely benign	Familial cancer of breast	2023-05-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003315869	SCV004204501	uncertain significance	Familial cancer of breast	2023-12-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000199094	SCV001461806	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing