ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.3150T>C (p.Leu1050=)

gnomAD frequency: 0.00076  dbSNP: rs3092859
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
Invitae RCV000122839 SCV000166097 benign Ataxia-telangiectasia syndrome 2021-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162639 SCV000213076 likely benign Hereditary cancer-predisposing syndrome 2014-07-28 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health RCV000162639 SCV000682105 likely benign Hereditary cancer-predisposing syndrome 2015-08-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679110 SCV000805533 benign not specified 2017-08-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000679110 SCV000916614 benign not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.3150T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0016 in 277234 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.009 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 9 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 Finnish origin. The variant c.3150T>C has been reported in the literature in individuals affected with breast or ovarian cancer (Heikkinen_2005). This report, however does not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, an internal sample reports the variant to co-occur with a likely pathogenic RAD51C variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services,Illumina RCV000122839 SCV001266173 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.
GeneDx RCV001640111 SCV001855318 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798391 SCV002042048 likely benign Breast and/or ovarian cancer 2021-05-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000679110 SCV002069395 likely benign not specified 2021-11-29 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000162639 SCV002533576 benign Hereditary cancer-predisposing syndrome 2020-07-31 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358528 SCV001554289 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Leu1050= variant was identified in 1 of 242 proband chromosomes (frequency: 0.004) from Finnish individuals or families with breast and/or ovarian cancer; and was present in 1 of 186 control chromosomes (frequency: 0.005) from lymphoblastoid cell lines from unselected individuals from major populations (Thorstenson 2001, Heikkinen 2005). The variant was also identified in dbSNP (ID: rs3092859) “With Likely benign” allele , ClinVar (classified benign by Invitae and likely benign by Ambry Genetics). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD database. The variant was identified in control databases in 439 (1 homozygous) of 277050 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu1050= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, but located 4 nucleotides from the 3’end of exon 21. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.