Submissions for variant NM_000051.4(ATM):c.3014A>G (p.Asn1005Ser)

gnomAD frequency: 0.00028  dbSNP: rs146531614

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588986	SCV000149080	uncertain significance	not provided	2017-11-14	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3014A>G at the cDNA level, p.Asn1005Ser (N1005S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been reported in individuals with personal histories of breast, ovarian, and pancreatic cancer (Grant 2015, Lu 2015, Tung 2016, Decker 2017). This variant was reported in a multiethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Asn1005Ser was observed at an allele frequency of 0.65% (66/10,142 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the beta-adaptin interaction domain (Tavtigian 2009). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn1005Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079613	SCV000166096	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115171	SCV000172766	benign	Hereditary cancer-predisposing syndrome	2015-05-14	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.
Genetic Services Laboratory, University of Chicago	RCV000194529	SCV000246615	likely benign	not specified	2019-08-15	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000194529	SCV000296850	uncertain significance	not specified	2015-10-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000588986	SCV000340770	uncertain significance	not provided	2016-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515446	SCV000611355	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194529	SCV000694245	benign	not specified	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3014A>G (p.Asn1005Ser) 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 0.00039 in 253746 control chromosomes (gnomAD and Weitzel_2019), predominantly in the Ashkenazi Jewish cohort at an allele frequency of 0.0065. This frequency is approximately 6.5 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 individuals of Ashkenazi Jewish origin. In addition, FLOSSIES (cohort of individuals older than 70 that never had cancer), this variant was also observed with an allele frequency of 0.0004047 (4/9884 individuals). c.3014A>G has been reported in the literature in individuals affected with breast cancer, ovarian cancer and in individuals with an increased risk of pancreatic cancer (Tung_2016, Lu _2015, Abe_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000115171	SCV000910569	likely benign	Hereditary cancer-predisposing syndrome	2014-12-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079613	SCV001263810	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515446	SCV001468411	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ATM NM_000051.3 exon 20 p.Asn1005Ser (c.3014A>G): This variant has been reported in the literature as germline in at least 3 individuals with cancer (Haiman 2013 PMID:23555315, Lu 2015 PMID:26689913, Tung 2016 PMID:26976419). This variant is present in 0.6% (65/10362) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108142070-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several conflicting interpretations between Variant of Uncertain Significance (VUS) and Likely Benign/Benign (Variation ID:127366). This variant amino acid Serine (Ser) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Sema4, Sema4	RCV000115171	SCV002535245	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000588986	SCV002544606	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	ATM: BP1, BP4
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291557	SCV002584595	uncertain significance	Familial cancer of breast	2022-08-30	criteria provided, single submitter	clinical testing	The ATM c.3014A>G (p.Asn1005Ser) missense change has a maximum subpopulation frequency of 0.048% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast cancer (PMID: 26976419). This variant has been reported in 4 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588986	SCV004220910	benign	not provided	2022-05-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492454	SCV004240502	uncertain significance	Breast and/or ovarian cancer	2023-05-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002291557	SCV005083941	likely benign	Familial cancer of breast	2024-05-13	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].
Mendelics	RCV004700416	SCV005205580	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004549545	SCV000805530	likely benign	ATM-related disorder	2019-09-10	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	RCV001354960	SCV001549695	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asn1005Ser variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung 2016). The variant was also identified in dbSNP (ID: rs146531614) as “With Uncertain significance allele”, ClinVar (classified as benign by Ambry Genetics; as likely benign by Invitae; as uncertain significance by GeneDx and 5 clinical laboratories), Clinvitae, MutDB, and LOVD 3.0 databases. The variant was not identified in the COGR, or the Cosmic database. The variant was identified in control databases in 100 of 277096 chromosomes at a frequency of 0.0004 variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24030 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 17 of 34418 chromosomes (freq: 0.001), European in 13 of 126614 chromosomes (freq: 0.0001), Ashkenazi Jewish in 66 of 10142 chromosomes (freq: 0.01); it was not observed in the East Asian, Finnish, and South Asian populations. The p.Asn1005 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 2 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV000588986	SCV001749644	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Benign and reported on 03-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115171	SCV002050314	benign	Hereditary cancer-predisposing syndrome	2021-11-09	no assertion criteria provided	clinical testing