Submissions for variant NM_000051.4(ATM):c.1960C>A (p.Gln654Lys)

gnomAD frequency: 0.00001  dbSNP: rs528165789

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122828	SCV000166085	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 654 of the ATM protein (p.Gln654Lys). This variant is present in population databases (rs528165789, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 12362033, 19781682, 24416720, 26976419, 28135145, 32853339). ClinVar contains an entry for this variant (Variation ID: 135739). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV000165083	SCV000215786	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The p.Q654K variant (also known as c.1960C>A), located in coding exon 12 of the ATM gene, results from a C to A substitution at nucleotide position 1960. The glutamine at codon 654 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in both breast cancer patients and healthy controls (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is 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.
GeneDx	RCV000254742	SCV000322091	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, prostate cancer, colon cancer, and cancer of unknown primary as well as unaffected controls (Maillet et al., 2002; Tavtigian et al., 2009; Petereit et al., 2013; Tung et al., 2016; Decker et al., 2017; Tiao et al., 2017; Yurgelun et al., 2017; Darst et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 28135145, 28652578, 19781682, 12362033, 24416720, 26976419, 28779002, 28717660, 32853339, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000165083	SCV000902998	likely benign	Hereditary cancer-predisposing syndrome	2017-01-30	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000254742	SCV002010843	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165083	SCV002533966	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254742	SCV002774760	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320097	SCV004024387	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467083	SCV004210152	uncertain significance	Familial cancer of breast	2024-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492531	SCV004240358	uncertain significance	Breast and/or ovarian cancer	2023-06-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467083	SCV005085810	likely benign	Familial cancer of breast	2024-05-02	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].
Natera, Inc.	RCV000122828	SCV001461087	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354480	SCV001549108	uncertain significance	Familial pancreatic carcinoma		no assertion criteria provided	clinical testing	The ATM p.Gln654Lys variant was identified in 4 of 3680 proband chromosomes (frequency: 0.001) from individuals or families with breast or colon cancer and was not identified in 280 control chromosomes from healthy individuals (Maillet 2002, Petereit 2013, Tung 2016, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs528165789) as "With Pathogenic, Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 7 of 246108 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 5 of 111600 chromosomes (freq: 0.00005), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gln654 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.