ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4402G>A (p.Val1468Ile) (rs369903995)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656760 SCV000149103 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.4402G>A at the cDNA level, p.Val1468Ile (V1468I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has been observed in an individual with MMR-proficient colorectal cancer (Pearlman 2017). ATM Val1468Ile was also identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. ATM Val1468Ile was observed at an allele frequency of 0.08% (18/23,982) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val1468Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115194 SCV000186529 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing The p.V1468I variant (also known as c.4402G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4402. The valine at codon 1468 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects. (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). Another study detected this alteration in 1/450 patients who were diagnosed with colorectal cancer under the age of 50 years (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656760 SCV000228684 uncertain significance not provided 2015-05-08 criteria provided, single submitter clinical testing
Invitae RCV000199082 SCV000254107 likely benign Ataxia-telangiectasia syndrome 2020-11-25 criteria provided, single submitter clinical testing
Mendelics RCV000199082 SCV000838540 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115194 SCV000911162 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120138 SCV000918526 uncertain significance not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: ATM c.4402G>A (p.Val1468Ile) results in a conservative amino acid change located in the Armadillo-type fold of 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 8.4e-05 in 250942 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. Another database, FLOSSIES, that contains unaffected individuals older than 70 years of age, observed the variant in 6/2559 African Americans, combining this data with the gnomAD occurrences could suggest the variant is a benign polymorphism found in populations of African origin. c.4402G>A has been reported in the literature in individuals affected with Breast Cancer (Pearlman_2017). This report does 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249853 SCV001424015 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-27 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that results in a valine to isoleucine amino acid change at residue 1468 in the ATM protein. This is a previously reported, rare variant in control population datasets (gnomAD database, 28/276692 alleles, 0 homozygotes, 0.01% overall frequency) and has been observed in a single colon cancer patient (PMID 27978560), but no published breast cancer cases, to our knowledge. The Val1468 residue is not located in a domain known to be critical for ATM function, and studies adequately assessing the effect of this variant on protein function have not been identified. The Val1468 residue is highly evolutionarily conserved among mammalian species examined. Bioinformatic tools queried are in disagreement with whether this amino acid change would be damaging. There are multiple entries in ClinVar for this variant, all of which assert a clinical significance that is uncertain. Based upon the evidence, we are in agreement that the clinical significance of this variant is uncertain.
Baylor Genetics RCV000199082 SCV001530023 uncertain significance Ataxia-telangiectasia syndrome 2018-04-19 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000120138 SCV000084278 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000199082 SCV001462324 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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.