ClinVar Miner

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

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Total submissions: 11
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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 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115171 SCV000172766 benign Hereditary cancer-predisposing syndrome 2015-05-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000194529 SCV000246615 likely benign not specified 2019-08-15 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The 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
Integrated Genetics/Laboratory Corporation of America RCV000194529 SCV000694245 likely benign not specified 2019-07-18 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 0.00038 in 251348 control chromosomes (gnomAD), 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. Seven ClinVar submissions (evaluation after 2014) cite the variant twice as benign, once as likely benign and four times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000588986 SCV000805530 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing
Color 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.

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