Submissions for variant NM_000051.4(ATM):c.4949A>G (p.Asn1650Ser)

gnomAD frequency: 0.00030  dbSNP: rs55870064

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589659	SCV000149109	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24951259, 19781682, 21787400, 17344846, 24728327, 26976419, 26787654, 26689913, 23555315, 21910157, 12969974, 26506520, 22529920, 20232390, 20305132, 28580595)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082738	SCV000166113	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115200	SCV000212953	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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)	RCV000120142	SCV000334654	benign	not specified	2015-08-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115200	SCV000682231	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120142	SCV000694294	benign	not specified	2021-09-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4949A>G (p.Asn1650Ser) 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 0.0012 in 304304 control chromosomes, predominantly at a frequency of 0.0073 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-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.4949A>G has been reported in the literature in individuals affected with different types of cancer including pediatric Hodgkins disease, breast cancer, gastric cancer, pancreatic cancer, biliary tract carcinoma, colorectal cancer and lung cancer (e.g. Takagi_2004, Tavtigian_2009, Bernstein_2010, Harismendy_2013, Grant_2015, Huang_2015, Lu_2015, Tung_2016, Toh_2018, Xie_2018, Terashima_2019) but it was also reported in a large number of controls (e.g. Shi_2011, Momozawa_2018). These data do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with pathogenic variants have been observed at our laboratory (RAD51D c.904-2A>T; ATM c.5712dupA, p.Ser1905fsX25; Internal testing), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function indicated that this variant provided insufficient complementation of radiosensitivity in ATM-null cells and that phosphorylation by this variant in ATM-competent cells was inhibited in a dominant-negative manner (Takagi_2004). The authors conclude that the function of this polymorphic variant is defective under heterozygous conditions, however, in our assessment, the in-vivo impact of this finding is not clearly established. Multiple ClinVar submitters (evaluation after 2014) cite the variant with complete consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics	RCV000589659	SCV000840943	likely benign	not provided	2020-03-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082738	SCV001264587	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589659	SCV001469354	likely benign	not provided	2020-03-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115200	SCV002527690	benign	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315636	SCV004015356	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120142	SCV004027233	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492460	SCV004239272	likely benign	Breast and/or ovarian cancer	2022-12-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315636	SCV005084039	likely benign	Familial cancer of breast	2024-05-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ITMI	RCV000120142	SCV000084282	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115200	SCV000787867	likely benign	Hereditary cancer-predisposing syndrome	2017-08-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589659	SCV001551223	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Asn1650Ser variant was identified in 63 of 23302 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer and was present in 220 of 52,260 control chromosomes (frequency: 0.005) from healthy individuals (Momozawa 2018, Tavtigian 2009, Tung 2016). The variant was identified in dbSNP (rs55870064) as “with uncertain significance, other allele”, ClinVar (classified as benign by Color, Invitae, Ambry Genetics and Eurofins; and as likely benign by GeneDx, Integrated Genetics, Athena Diagnostics and True Health Diagnostics) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 159 of 282,444 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 148 of 19,934 chromosomes (freq: 0.007, increasing the likelihood this could be a low frequency benign variant), Other in 3 of 7208 chromosomes (freq: 0.0004), African in 6 of 24,966 chromosomes (freq: 0.0002), Latino in 1 of 35,432 chromosomes (freq: 0.00003), and European in 1 of 128,834 chromosomes (freq: 0.000008); it was not observed in the Ashkenazi Jewish, Finnish or South Asian populations. This variant has been identified by our laboratory in a patient with a co-occurring, pathogenic ATM variant (c.8288del, p.Arg2763Glnfs*43), who was not affected by ataxia telangiectasia, and in another patient with a co-occurring, pathogenic BRCA2 variant (c.4940_4941del, p.Thr1647Serfs*18), decreasing the likelihood that this variant has clinical significance. The p.Asn1650 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 although 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this information is not very predictive of pathogenicity. 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 Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000589659	SCV001905770	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589659	SCV001957087	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589659	SCV001970527	likely benign	not provided		no assertion criteria provided	clinical testing