Submissions for variant NM_000051.4(ATM):c.1844T>C (p.Leu615Pro)

dbSNP: rs786203783

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167236	SCV000218073	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	The p.L615P variant (also known as c.1844T>C), located in coding exon 11 of the ATM gene, results from a T to C substitution at nucleotide position 1844. The leucine at codon 615 is replaced by proline, an amino acid with similar properties. This variant was identified in conjunction with other pathogenic variants in ATM in multiple individuals diagnosed with ataxia-telangiectasia (Schon K et al. Ann Neurol 2019 02;85(2):170-180; Seo GH et al. Clin Genet 2020 12;98(6):562-570). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000167236	SCV000682006	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 615 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous state in an individual affected with autosomal recessive variant ataxia-telangiectasia (PMID: 26896183, 30549301), indicating that this variant contributes to disease. This variant has been reported in trans with a variant of uncertain significance, c.8687A>C (p.Gln2896Pro), in a second individual affected with ataxia-telangiectasia (PMID: 32901917). In addition, this variant has been observed in individuals affected with prostate cancer (PMID: 29368341). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819663	SCV000960336	likely pathogenic	Ataxia-telangiectasia syndrome	2023-05-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 187501). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or prostate cancer (PMID: 29368341, 30549301, 32901917; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 615 of the ATM protein (p.Leu615Pro).
3billion	RCV000819663	SCV002012329	likely pathogenic	Ataxia-telangiectasia syndrome	2021-10-02	criteria provided, single submitter	clinical testing	It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed in trans with a pathogenic variant [NM_000051.3:c.8687A>C (p.Gln2896Pro)] as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.792, PP3). Patient's phenotype is considered compatible with Ataxia-telangiectasia (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444209	SCV004171397	likely pathogenic	Familial cancer of breast	2023-11-07	criteria provided, single submitter	clinical testing	The ATM c.1844T>C (p.Leu615Pro) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been observed in trans with a pathogenic variant [NM_000051.3:c.8687A>C (p.Gln2896Pro)] in at least one patient with ataxia telangiectasia (PMID: 26896183, 30549301, 32901917). ATM expression and ATM activity assays performed on a lymphoblastoid cell line derived from the patient’s blood demonstrated residual kinase activity. In addition, the in silico tool REVEL predicts a deleterious effect on protein function. This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic.
Baylor Genetics	RCV003444209	SCV004209531	likely pathogenic	Familial cancer of breast	2023-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV004721285	SCV005327063	likely pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Identified in an individual with prostate cancer (PMID: 29368341); 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: 32901917, 30549301, 29368341, 26896183)
Natera, Inc.	RCV000819663	SCV002076156	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-20	no assertion criteria provided	clinical testing