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

gnomAD frequency: 0.00076  dbSNP: rs3092859

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122839	SCV000166097	benign	Ataxia-telangiectasia syndrome	2024-01-31	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, part of Exact Sciences	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000679110	SCV002760548	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001640111	SCV002774014	benign	not provided	2022-12-05	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315806	SCV004015455	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001640111	SCV004701281	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATM: BP4
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.