Submissions for variant NM_000051.4(ATM):c.7919C>T (p.Thr2640Ile)

gnomAD frequency: 0.00011  dbSNP: rs4988125

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130402	SCV000185262	likely benign	Hereditary cancer-predisposing syndrome	2019-05-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000586791	SCV000209649	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast or other cancers and in healthy controls (PMID: 19781682, 24728327, 25186627, 27720647, 28779002, 28873162, 30287823, 30426508, 34326862, 33471991, 34359559); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 24728327, 22529920, 26976419, 27720647, 28779002, 28873162, 20305132, 30287823, 29642553, 29522266, 21346221, 30447919, 34359559, 33471991, 30426508, 34262154, 25186627, 34326862, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168144	SCV000218804	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120159	SCV000694364	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7919C>T (p.Thr2640Ile) 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 8.9e-05 in 304866 control chromosomes (gnomAD and publication data). This frequency is not higher than the estimated maximal expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. The variant, c.7919C>T, has been reported in the literature in individuals affected with breast cancer (e.g. Bernstein_2010, Tung_2014, Hauke_2018, Schubert_2019), however it was also found in several controls (e.g. Tavtigian_2009, Momozawa_2018, Dalmasso_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 25/60466 cases, but was also found in 16/53461 controls (Dorling_2021, reported through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 20305132, 24728327, 34262154, 33471991, 22529920, 21346221, 29522266, 30287823, 30426508, 19781682, 25186627, 30447919). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=6) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168144	SCV000745133	likely benign	Ataxia-telangiectasia syndrome	2017-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000586791	SCV000805621	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130402	SCV000910632	likely benign	Hereditary cancer-predisposing syndrome	2014-12-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130402	SCV002537767	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130402	SCV002819248	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120159	SCV004024719	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325183	SCV004031154	uncertain significance	Familial cancer of breast	2023-08-30	criteria provided, single submitter	clinical testing	The ATM c.7919C>T (p.Thr2640Ile) missense change has a maximum subpopulation frequency of 0.02% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 25186627, 28779002, 29522266). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000586791	SCV004133277	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ATM: BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000586791	SCV004226242	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	BP4
Myriad Genetics, Inc.	RCV003325183	SCV005083969	likely benign	Familial cancer of breast	2024-06-17	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].
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV004724814	SCV005205814	uncertain significance	Tip-toe gait	2024-07-31	criteria provided, single submitter	clinical testing
ITMI	RCV000120159	SCV000084301	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000168144	SCV000732996	likely benign	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355591	SCV001550517	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr2640Ile variant was identified in 1 of 1102 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer and was present in 2 of 24980 control chromosomes (frequency: 0.00008) from healthy individuals (Momozawa 2018, Tung 2016). The variant was also identified in dbSNP (ID: rs4988125) as "With Likely benign, other allele", ClinVar (classified as likely benign by two submitters; and as uncertain significance by Invitae, GeneDx, Ambry Genetics and two other submitters), and in LOVD 3.0 (3x). The variant was identified in control databases in 28 of 275836 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 26 of 126328 chromosomes (freq: 0.0002) and Finnish in 2 of 24916 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Thr2640 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586791	SCV001807373	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586791	SCV001957297	likely benign	not provided		no assertion criteria provided	clinical testing