ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3919G>A (p.Gly1307Arg) (rs568451087)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131248 SCV000186209 likely benign Hereditary cancer-predisposing syndrome 2019-02-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000234723 SCV000282946 benign Ataxia-telangiectasia syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV001704057 SCV000729394 likely benign not provided 2020-11-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131248 SCV000910688 benign Hereditary cancer-predisposing syndrome 2016-10-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000234723 SCV001260528 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000608362 SCV001437333 likely benign not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: ATM c.3919G>A (p.Gly1307Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251256 control chromosomes, predominantly at a frequency of 0.0029 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-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 South Asian origin. c.3919G>A has been reported in the literature in individuals affected with cancer including low grade glioma and breast cancer (e.g. Shayeghi_1998, Lu_2015, Mandelker_2017) but was also reported in non-cancer controls (e.g. Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One submitter in LOVD reports co-occurrence of the variant with 2 undefined pathogenic variants and classifies it as benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356054 SCV001551112 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Gly1307Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs568451087) as "With Likely benign allele", ClinVar (classified as likely benign by Ambry Genetics, Invitae, and GeneDx), and LOVD 3.0 (1x) databases. The variant was identified in control databases in 94 of 276986 chromosomes (2 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: South Asian in 92 of 30782 chromosomes (freq: 0.003), Other in 1 of 6458 chromosomes (freq: 0.0002), and East Asian in 1 of 18852 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, or Finnish populations. The p.Gly1307 residue is not conserved in mammals and four out of five 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.