Submissions for variant NM_000051.4(ATM):c.3161C>G (p.Pro1054Arg)

gnomAD frequency: 0.01452  dbSNP: rs1800057

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119124	SCV000153838	benign	Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130988	SCV000185910	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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)	RCV000120131	SCV000227871	benign	not specified	2015-02-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130988	SCV000292102	benign	Hereditary cancer-predisposing syndrome	2014-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120131	SCV000301660	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001538534	SCV000602551	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000119124	SCV000797292	benign	Ataxia-telangiectasia syndrome	2018-01-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000119124	SCV001138484	benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119124	SCV001266174	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.
Genome-Nilou Lab	RCV000119124	SCV001750396	benign	Ataxia-telangiectasia syndrome	2021-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001538534	SCV001756200	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30957677, 31382929, 26122175, 18502988, 24728327, 27599564, 27153395, 10464642, 17502119, 22529920, 21833744, 19431188, 23585524, 15101044, 11996792, 20826828, 23125224)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225346	SCV002505344	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130988	SCV002533609	benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120131	SCV002549988	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315702	SCV004016597	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315702	SCV005083886	benign	Familial cancer of breast	2024-05-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics	RCV001538534	SCV005216390	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120131	SCV000084270	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000130988	SCV000787859	benign	Hereditary cancer-predisposing syndrome	2018-01-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357969	SCV001553584	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Pro1054Arg variant was identified in both proband chromosomes (frequency not specified) from Swiss, Brazilian and European individuals or families with (early onset or sporadic) breast cancers, and in control chromosomes (frequency not specified) from healthy individuals (Mangone 2015, Milne 2009, Maillet 2002), increasing the likelihood this variant is not associated with breast cancer. Genotyping of 5 polymorphisms (with MAF 0.9-2.6%) including this variant in a large case control study, showed that the 5 missense polymorphisms were associated with a small increased risk of breast cancer (Fletecher 2010). The variant was confirmed to be associated with an increased risk of prostate cancer in a cohort of prostate cancer cases, being identified in 50 of 522 proband chromosomes (frequency 0.096), and 22 of 920 healthy controls were found to be carriers (1 homozygous, frequency: 0.024, Meyer 2007). The variant was identified in dbSNP (ID: rs1800057) as “With Benign allele”, Clinvitae database (classified as benign), ClinVar database (classification benign by Ambry Genetics, Emory Genetics, Color Genomics Inc, Prevention Genetics, Invitae and not classified by ITMI), and in COSMIC (in a squamous cell carcinoma, and lymphoid neoplasm-Burkitt lymphoma). The variant was also identified in LOVD 3.0 (2x) databases, but not in the ATM-LOVD database. The variant was identified in control databases in 4511 of 277018 chromosomes at a frequency of 0.016284 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 3306 of 126596 chromosomes (freq: 0.026), Ashkenazi Jewish in 224 of 10148 chromosomes (freq: 0.022), Other in 122 of 6458 chromosomes (freq: 0.019), Latino in 390 of 34412 chromosomes (freq: 0.011). The p.Pro1054 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs 8 nucleotides from the intron-exon junction and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.