Submissions for variant NM_000051.4(ATM):c.3963G>A (p.Met1321Ile)

gnomAD frequency: 0.00002  dbSNP: rs35184530

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129195	SCV000183934	likely benign	Hereditary cancer-predisposing syndrome	2018-09-24	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079506	SCV000547072	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000657024	SCV000566628	likely benign	not provided	2020-11-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28580595, 30287823, 25656989, 28256603, 25742471, 22529920, 26667234, 26787654, 19781682, 17344846, 24728327)
Color Diagnostics, LLC DBA Color Health	RCV000129195	SCV000910722	likely benign	Hereditary cancer-predisposing syndrome	2015-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120136	SCV001572374	likely benign	not specified	2021-04-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3963G>A (p.Met1321Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251186 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3963G>A has been reported in the literature in individuals affected with Breast Cancer and in unaffected controls (example, Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of benign/likely benign (n=4) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000120136	SCV002068120	uncertain significance	not specified	2020-05-07	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.3963G>A, in exon 26 that results in an amino acid change, p.Met1321Ile. This sequence change has been described in the gnomAD database with a frequency of 0.14% in the East Asian sub-population (dbSNP rs35184530). The p.Met1321Ile change has been identified in an individual with breast cancer (PMID:28580595). The p.Met1321Ile change affects a poorly conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Met1321Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met1321Ile change remains unknown at this time.
Sema4, Sema4	RCV000129195	SCV002536673	likely benign	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492517	SCV004240613	likely benign	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
ITMI	RCV000120136	SCV000084275	not provided	not specified	2013-09-19	no assertion provided	reference population
King Laboratory, University of Washington	RCV000120136	SCV001251386	benign	not specified	2019-09-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355120	SCV001549909	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Met1321Ile variant was identified in 2 of 19,164 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 9 of 51,952 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Tavtigian 2009). The variant was identified in dbSNP (rs35184530) as “with uncertain significance”, ClinVar (classified as uncertain significance by Invitae and GeneDx and likely benign by Ambry Genetics and Color) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 30 of 282,578 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 28 of 19,938 chromosomes (freq: 0.001), South Asian in 1 of 30612 chromosomes (freq: 0.00003), European in 1 of 128,956 chromosomes (freq: 0.000008), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish and Other populations. The p.Met1321 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) 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.	RCV001079506	SCV002081559	likely benign	Ataxia-telangiectasia syndrome	2020-02-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551178	SCV004724742	likely benign	ATM-related disorder	2022-04-22	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).