Submissions for variant NM_000051.4(ATM):c.103C>T (p.Arg35Ter)

dbSNP: rs55861249

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130278	SCV000185123	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	clinical testing	The p.R35* pathogenic mutation (also known as c.103C>T), located in coding exon 2 of the ATM gene, results from a C to T substitution at nucleotide position 103. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been previously reported in a homozygous state in multiple individuals of North African Jewish ancestry with ataxia-telangiectasia (A-T). Additionally, the allele frequency in North African Jewish individuals with A-T has been reported at 97%, as compared to 29% in the healthy North African Jewish population, strongly indicating a founder effect in this population (Gilad S et al. Hum. Mol. Genet. 1996 Dec;5:2033-7). The p.R35* mutation was subsequently identified in both Hispanic and Sephardic Jewish A-T families sharing the same SNP haplotype, suggesting that this mutation has spread to other ethnicities over time as a result of migration (Campbell C et al. Hum. Mutat. 2003 Jan;21:80-5). Furthermore, functional studies show that this mutation leads to the elimination of ATM protein synthesis (Gilad S et al. Hum. Mol. Genet. 1996 Dec;5:2033-7) as well as increased radiosensitivity (Gutiérrez-Enríquez S et al. Genes Chromosomes Cancer. 2004 Jun;40:109-19) in lymphoblastoid cell lines homozygous for this mutation. In addition to patients with ataxia-telangiectasia, this alteration has also been reported in breast, prostate and pancreatic cancer cohorts (Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genetic Services Laboratory, University of Chicago	RCV000003164	SCV000246611	pathogenic	Ataxia-telangiectasia syndrome	2014-06-27	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130278	SCV000266013	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000236608	SCV000293091	pathogenic	not provided	2022-03-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of ATM protein and reduced cell survival when exposed to radiation compared to wild-type (Fernet 2003); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 8968760, 23322442, 12673797, 35154108, 29922827, 30549301, 30274973, 15101044, 10873394, 12815592, 12497634, 10330348, 9450906, 26778106, 12072877, 14695997, 18171990, 12745884, 28152038, 29506128, 31741144, 29915382, 31447099, 26896183, 33436325, 32338768)
Counsyl	RCV000003164	SCV000485098	pathogenic	Ataxia-telangiectasia syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515417	SCV000611163	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130278	SCV000681949	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in many individuals affected with ataxia telangiectasia (PMID: 8968760, 9450906, 10873394, 12072877, 12815592, 21665257, 35154108) and has been described as a recurrent mutation in the North African Jewish population (PMID: 8968760). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). Cells derived from the carriers have shown increased radiosensitivity (PMID: 15101044, 17699107). This variant has been identified in 5/251230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003164	SCV000826949	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg35*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs55861249, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) and/or breast cancer (PMID: 8968760, 21665257, 26845104). It is commonly reported in individuals of North African Jewish ancestry (PMID: 8968760). ClinVar contains an entry for this variant (Variation ID: 3025). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 8968760, 12637545, 15101044, 17699107). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000003164	SCV000838465	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000236608	SCV000854897	pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003164	SCV000916531	pathogenic	Ataxia-telangiectasia syndrome	2018-05-09	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: The ATM c.103C>T (p.Arg35X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.513C>G, p.Tyr171X; c.790delT, p.Tyr264fsX12; c.1027_1030delGAAA, p.Glu343fsX2). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/246618 control chromosomes at a frequency of 0.0000324, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant was reported in numerous affected individuals in the literature, and is known as a North African Jewish founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236608	SCV001447901	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000236608	SCV001502086	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
3billion	RCV000003164	SCV002521644	pathogenic	Ataxia-telangiectasia syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003025 / PMID: 8968760). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Sema4, Sema4	RCV000130278	SCV002529696	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	curation
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236608	SCV004026075	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	PVS1
Baylor Genetics	RCV003466790	SCV004209446	pathogenic	Familial cancer of breast	2024-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003466790	SCV004932583	pathogenic	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003466790	SCV005038979	pathogenic	Familial cancer of breast	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg35*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs55861249, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) and/or breast cancer (PMID: 8968760, 21665257, 26845104). It is commonly reported in individuals of North African Jewish ancestry (PMID: 8968760). ClinVar contains an entry for this variant (Variation ID: 3025). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 8968760, 12637545, 15101044, 17699107). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000003164	SCV000023322	pathogenic	Ataxia-telangiectasia syndrome	1996-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000003164	SCV000328289	pathogenic	Ataxia-telangiectasia syndrome	2016-10-27	no assertion criteria provided	literature only
Natera, Inc.	RCV000003164	SCV001461804	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing