Submissions for variant NM_000051.4(ATM):c.3137T>C (p.Leu1046Pro)

dbSNP: rs568461905

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221504	SCV002499299	likely pathogenic	Familial cancer of breast	2022-03-16	reviewed by expert panel	curation	The ATM c.3137T>C (p.Leu1046Pro) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico protein predictors (REVEL Impact: 0.854; Align-GVGD: C65) predict that this alteration is deleterious (PP3). This variant has also been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with ataxia-telangiectasia (PMIDs: 27664052, 31429931) (PM3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Ambry Genetics	RCV000166173	SCV000216948	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-21	criteria provided, single submitter	clinical testing	The p.L1046P variant (also known as c.3137T>C), located in coding exon 20 of the ATM gene, results from a T to C substitution at nucleotide position 3137. The leucine at codon 1046 is replaced by proline, an amino acid with similar properties. This alteration has been detected in a homozygous state in a patient with consistent features of ataxia telangiectasia (A-T), as well as in a compound heterozygous state with a frameshift mutation in a patient with a clinical diagnosis of A-T (Shakya S et al. Clin Genet, 2019 12;96:566-574; Carranza D et al. Neuromolecular Med, 2017 Mar;19:161-174). In addition, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl	RCV000667954	SCV000792486	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667954	SCV000823337	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1046 of the ATM protein (p.Leu1046Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 27664052; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 186558). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters ATM gene expression (PMID: 27664052). This variant disrupts the p.Leu1046 amino acid residue in ATM. Other variant(s) that disrupt this residue have been observed in individuals with ATM-related conditions (PMID: 19535770), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166173	SCV000913918	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 1046 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a large international case-control meta-analysis, this variant was reported in 1/60465 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant was reported in the homozygous state in an individual with clinical features of ataxia-telangiectasia (PMID: 31429931). This variant has also been reported in the compound heterozygous state with a pathogenic truncation variant, c.640del (p.Ser214Profs*16), in an individual affected with ataxia-telangiectasia (PMID: 27664052). Cells derived from this individual showed no detectable protein expression and increased radiosensitivity compared to controls (PMID: 27664052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Suma Genomics	RCV000667954	SCV002097335	likely pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001795288	SCV004184189	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ATM: PM3:Strong, PM2, PS3:Supporting, BP1
Baylor Genetics	RCV002221504	SCV004207473	likely pathogenic	Familial cancer of breast	2024-03-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001795288	SCV005325733	likely pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	Reported in an individual with breast cancer in published literature (PMID: 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 19781682, 31429931, 27664052, 33471991)
Natera, Inc.	RCV000667954	SCV001452063	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001795288	SCV002035025	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001795288	SCV002035286	likely pathogenic	not provided		no assertion criteria provided	clinical testing