Submissions for variant NM_000051.4(ATM):c.202A>G (p.Ile68Val)

gnomAD frequency: 0.00004  dbSNP: rs35389822

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587881	SCV000149057	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast, pancreatic, or other cancers as well as in controls (PMID: 16832357, 19781682, 24416720, 28726808, 29641532, 35047863, 34326862); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22529920, 24416720, 27720647, 19781682, 28726808, 16832357, 30851065, 29641532, 35047863, 34326862)
Ambry Genetics	RCV000115148	SCV000185268	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	The p.I68V variant (also known as c.202A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 202. The isoleucine at codon 68 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1/302 patients with personal and family histories of pancreatic cancer (Chaffee KG et al. Genet. Med. 2018 01;20:119-127). This alteration has also been identified in unaffected control cohorts in multiple studies (Renwick A et al. Nat. Genet., 2006 Aug;38:873-5; Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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	RCV000199503	SCV000254067	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 68 of the ATM protein (p.Ile68Val). This variant is present in population databases (rs35389822, gnomAD 0.006%). This missense change has been observed in individual(s) with pancreatic or undefined cancer (PMID: 24416720, 28726808, 35047863). ClinVar contains an entry for this variant (Variation ID: 127344). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515328	SCV000611348	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587881	SCV000694207	uncertain significance	not provided	2016-09-06	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.202A>G (p.Ile68Val) variant involves the alteration of a conserved nucleotide. Ile68 is not conserved across species and is not located in a known functional domain; 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/102164 control chromosomes at a frequency of 0.0000294, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was identified in only one cancer patient reported in the literature, however, no clinical or co-segregation data was provided, thus its implication in this patients cancer diagnosis cannot be assessed (Petereit_2013). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl	RCV000199503	SCV000791981	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115148	SCV000902983	likely benign	Hereditary cancer-predisposing syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000587881	SCV001143099	uncertain significance	not provided	2019-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149792	SCV003838923	uncertain significance	Breast and/or ovarian cancer	2021-09-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467020	SCV004209544	uncertain significance	Familial cancer of breast	2024-02-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467020	SCV005083862	likely benign	Familial cancer of breast	2024-04-18	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].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003467020	SCV005402307	uncertain significance	Familial cancer of breast	2024-04-19	criteria provided, single submitter	clinical testing	The ATM c.202A>G (p.Ile68Val) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355668	SCV001550618	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Ile68Val variant was identified in 1 of 16,852 proband chromosomes (frequency: 0.00006) from an individual with cancer and was present in 1 of 4798 control chromosomes (frequency: 0.0002) from healthy individuals (Petereit 2013, Tavtigian 2009). The variant was identified in dbSNP (rs35389822) as “with uncertain significance allele and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl, GeneDx and 2 other submitters; and as likely benign by Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 8 of 275,380 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 125,734 chromosomes (freq: 0.00006), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Ile68 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.
Natera, Inc.	RCV000199503	SCV002088277	uncertain significance	Ataxia-telangiectasia syndrome	2021-04-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739387	SCV005352464	uncertain significance	ATM-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The ATM c.202A>G variant is predicted to result in the amino acid substitution p.Ile68Val. This variant has been reported in an individual with pancreatic cancer and in a individual with an unspecified cancer (Table S2, Chaffee et al. 2018. PubMed ID: 28726808; Petereit et al. 2013. PubMed ID: 24416720). It has also been reported in controls from two cancer cohort studies (Table S2, Renwick et al. 2006. PubMed ID: 16832357; Supplement, Pritchard et al. 2018. PubMed ID: 29641532). In the gnomAD public population database this variant has been reported in up to 0.0063% of alleles in a subpopulation and has conflicting interpretations regarding its pathogenicity in ClinVar ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127344/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.