Submissions for variant NM_000051.4(ATM):c.1229T>C (p.Val410Ala)

gnomAD frequency: 0.00186  dbSNP: rs56128736

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120171	SCV000149045	benign	not specified	2016-11-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119195	SCV000153936	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115136	SCV000172873	benign	Hereditary cancer-predisposing syndrome	2014-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000120171	SCV000232902	likely benign	not specified	2015-04-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000115136	SCV000266989	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120171	SCV000593497	likely benign	not specified	2020-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115136	SCV000681959	benign	Hereditary cancer-predisposing syndrome	2015-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590142	SCV000694174	likely benign	not provided	2016-06-10	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1229T>C (p.Val410Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 270/126714 control chromosomes (2 homozygotes) at a frequency of 0.0021308, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this variant is likely a benign polymorphism. This variant has been found in patients with various types of cancer, including breast cancer, uterine serous carcinoma, lymphoma, chronic lymphocytic leukemia, and melanoma. It has not been reported in patients with ataxia-telangiectasia. Two large case-control studies showed that this variant is not associated with breast cancer (Tavtigian 2009; Haiman 2013). Thus available patient and control data show that this variant is a polymorphism found in patients as well as unaffected individuals. In addition, three clinical laboratories have classified this variant as benign/likely benign albeit another lab consider it as uncertain significance, all without evidence to independently evaluate. Taken together, this variant has been classified as Likely benign until more evidence becomes available.
CeGaT Center for Human Genetics Tuebingen	RCV000590142	SCV000780400	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: BS2
Counsyl	RCV000119195	SCV000788575	likely benign	Ataxia-telangiectasia syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115136	SCV000803142	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000590142	SCV000840914	benign	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000119195	SCV001138445	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590142	SCV001157044	benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119195	SCV001263700	likely benign	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000119195	SCV001439181	likely benign	Ataxia-telangiectasia syndrome	2020-08-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590142	SCV001714393	uncertain significance	not provided	2019-04-21	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590142	SCV002010846	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798307	SCV002042185	likely benign	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115136	SCV002530198	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120171	SCV002760519	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120171	SCV002774006	benign	not specified	2021-11-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589555	SCV005083837	likely benign	Familial cancer of breast	2024-04-25	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].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000590142	SCV005199603	likely benign	not provided	2022-05-27	criteria provided, single submitter	clinical testing
ITMI	RCV000120171	SCV000084313	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115136	SCV000787842	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549538	SCV000805492	likely benign	ATM-related disorder	2024-02-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356635	SCV001551859	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Val410Ala variant was identified in 5 of 1492 proband chromosomes (frequency: 0.003) from Dutch and Austrian individuals or families with breast cancer or ovarian cancer, and individuals with pediatric ALL (acute lymphocytic leukemia), and was identified in 2 of 644 chromosomes (frequency: 0.003) from healthy individuals (Broeks_2008_17393301, Thorstenson_2003_12810666, Liberzon_2004_14695997). The variant was also identified as a somatic mutation in 2 studies screening CRCs and lymphomas (Dallol_2016_ 27146902, Fang_2003_12149228). The variant was identified in dbSNP (ID: rs56128736) “With other allele”, ClinVar (wth conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics, GeneDx, and Invitae, likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), uncertain significance by Vantari Genetics and Genetic Services Laboratory (University of Chicago), and classification not provided by ITMI), Clinvitae (4x), Cosmic (7x in malignant melanoma, lymphoid neoplasm and carcinoma of the lung), LOVD 3.0, and in control databases in 582 (3 homozygous) of 276862 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 18 of 24018 chromosomes (freq: 0.0007), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 105 of 34390 chromosomes (freq: 0.003), European Non-Finnish in 401 (2 homozygous) of 126452 chromosomes (freq: 0.003), Ashkenazi Jewish in 41 (1 homozygous) of 10138 chromosomes (freq: 0.004), European Finnish in 3 of 25762 chromosomes (freq: 0.0001), while not observed in the East Asian and South Asian populations. The variant was not identified in GeneInsight-COGR or MutDB. The p.Val410 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ala 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, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590142	SCV001980136	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119195	SCV002092846	benign	Ataxia-telangiectasia syndrome	2020-01-15	no assertion criteria provided	clinical testing