ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3014A>G (p.Asn1005Ser) (rs146531614)

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Total submissions: 14
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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.
Invitae RCV001079613 SCV000166096 benign Ataxia-telangiectasia syndrome 2020-12-07 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: 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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.
PreventionGenetics,PreventionGenetics RCV000588986 SCV000805530 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115171 SCV000910569 likely benign Hereditary cancer-predisposing syndrome 2014-12-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2020-09-30 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 ( 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.
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.

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