Submissions for variant NM_000051.4(ATM):c.3467C>T (p.Thr1156Met)

gnomAD frequency: 0.00004  dbSNP: rs759951393

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162792	SCV000213270	likely benign	Hereditary cancer-predisposing syndrome	2018-03-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167875	SCV000218521	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1156 of the ATM protein (p.Thr1156Met). This variant is present in population databases (rs759951393, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682, 26976419). ClinVar contains an entry for this variant (Variation ID: 183918). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000478106	SCV000566875	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history of breast cancer but also in healthy controls (PMID: 19781682, 26976419, 28779002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 21787400, 26976419, 27150160, 28779002, 28652578, 29684080, 30979843)
Color Diagnostics, LLC DBA Color Health	RCV000162792	SCV000911161	likely benign	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551382	SCV004104667	uncertain significance	ATM-related disorder	2023-09-08	criteria provided, single submitter	clinical testing	The ATM c.3467C>T variant is predicted to result in the amino acid substitution p.Thr1156Met. This variant has been reported alone and along with another ATM variant in individuals with breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A2, Tung et al. 2016. PubMed ID: 26976419). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108151786-C-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/183918/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479031	SCV004222724	uncertain significance	not specified	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3467C>T (p.Thr1156Met) 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 1.6e-05 in 251348 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3467C>T has been reported in the literature in individuals affected with Breast Cancer (example, Tavtigian__2009). These report(s) do not provide unequivocal conclusions about association of the variant with ATM-associated Breast Cancer or Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 26976419). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=2 VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354530	SCV001549172	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr1156Met variant was identified in 2 of 6038 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and was not identified in 4490 control chromosomes from healthy individuals (Tavtigian 2009, Tung 2016). The variant was also identified in dbSNP (ID: rs759951393) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 5 of 277108 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 126638 chromosomes (freq: 0.00004), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Thr1156 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.