Submissions for variant NM_000051.4(ATM):c.5089A>G (p.Thr1697Ala)

gnomAD frequency: 0.00014  dbSNP: rs142455912

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212027	SCV000149114	uncertain significance	not provided	2023-08-27	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; Published functional studies suggest no damaging effect: lymphoblastoid cell line showed normal constitutive ATM protein level (Angele et al., 2003); This variant is associated with the following publications: (PMID: 19683821, 27150160, 26350204, 26787654, 26689913, 19781682, 28135145, 25186627, 28779002, 30197789, 28652578, 30979843, 30972172, 12473594, 33395407, 28843361, 14695186, 32885271, 35047863)
Ambry Genetics	RCV000115205	SCV000184397	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	The p.T1697A variant (also known as c.5089A>G), located in coding exon 33 of the ATM gene, results from an A to G substitution at nucleotide position 5089. The threonine at codon 1697 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in 3/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
Invitae	RCV000200336	SCV000254119	likely benign	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515379	SCV000611366	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549556	SCV000805578	uncertain significance	ATM-related disorder	2023-10-19	criteria provided, single submitter	clinical testing	The ATM c.5089A>G variant is predicted to result in the amino acid substitution p.Thr1697Ala. This variant has previously been reported in individuals with breast cancer (Tavtigian et al. 2009, Table S2. PubMed ID: 19781682), colorectal cancer (Yurgelun et al. 2017. PubMed ID: 28135145), and Hodgkin’s disease (Offit et al. 2002. PubMed ID: 12473594). However, a functional study involving this variant revealed unaltered constitutive protein levels compared to wild type (Angèle et al. 2003. PubMed ID: 14695186). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108170524-A-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127400/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV000115205	SCV000902827	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779803	SCV000916607	uncertain significance	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5089A>G (p.Thr1697Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 254138 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.3e-05 vs 0.004), allowing no conclusion about variant significance. c.5089A>G has been reported in the literature in individuals affected with Hodgkins disease, breast cancer, colorectal cancer, lung adenocarcinoma, and CLL (Offit_2002, Angele_2003, Tavtigian_2009, Tung_2015, Lu_2015, Young_2015, Yurgelun_2017, Tiao_2017, Parry_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or susceptibility to breast or other cancers. One publication reports experimental evidence showing that the cell lines from the breast cancer patient carrying c.5089A>G showed no differences in the constitutive ATM protein level (Angele_2003) although the authors did not provide any primary data substantiating this observation. The following publications have been ascertained in the context of this evaluation (PMID: 14695186, 26689913, 12473594, 28843361, 19781682, 28652578, 25186627, 26787654, 28135145). ClinVar contains an entry for this variant (Variation ID: 127400). Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798319	SCV002042668	uncertain significance	Breast and/or ovarian cancer	2020-03-11	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225320	SCV002504730	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589568	SCV005084063	likely benign	Familial cancer of breast	2024-05-22	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354115	SCV001548649	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr1697Ala variant was identified in 4 of 5698 proband chromosomes (frequency: 0.0007) from individuals or families with breast cancer or Hodgkin’s Disease and was not identified in 624 control chromosomes from healthy individuals (Angele 2003, Offit 2002, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs142455912) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and one clinical laboratory). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 12 of 276948 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24030 chromosomes (freq: 0.00004), Latino in 1 of 34416 chromosomes (freq: 0.00003), European in 10 of 126462 chromosomes (freq: 0.00008), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr1697 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) 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.