Submissions for variant NM_000051.4(ATM):c.5144T>C (p.Leu1715Pro)

gnomAD frequency: 0.00001  dbSNP: rs747800057

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233443	SCV000282980	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-19	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 1715 of the ATM protein (p.Leu1715Pro). This variant is present in population databases (rs747800057, gnomAD 0.0009%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or pancreatic cancer (PMID: 26896183, 30819809, 35047863). ClinVar contains an entry for this variant (Variation ID: 236730). 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. 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	RCV000481313	SCV000565974	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: similar to wild type controls in a phosphorylation assay (Fievet 2019); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the compound heterozygous state with a pathogenic ATM variant in siblings, one of which has exhibited clinical features suggestive of ataxia telangiectasia (Fievet 2019, van Os 2019); This variant is associated with the following publications: (PMID: 25742471, 31050087, 30819809)
Color Diagnostics, LLC DBA Color Health	RCV000579553	SCV000682250	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 1715 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). This variant has been observed in the compound heterozygous state and homozygous state in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 26896183, 30819809, 31050087), indicating that this variant contributes to disease. Cells derived from one of these individuals showed phosphorylation activity comparable to healthy controls (PMID: 31050087). This variant has been identified in 1/251094 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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.
Ambry Genetics	RCV000579553	SCV001185516	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-23	criteria provided, single submitter	clinical testing	The p.L1715P variant (also known as c.5144T>C), located in coding exon 33 of the ATM gene, results from a T to C substitution at nucleotide position 5144. The leucine at codon 1715 is replaced by proline, an amino acid with similar properties. This alteration has been reported in the homozygous state and in conjunction with a likely pathogenic or pathogenic ATM variant in individuals diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7; van Os NJH et al. J Med Genet, 2019 05;56:308-316; Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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.
Baylor Genetics	RCV003469127	SCV004209461	likely pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003469127	SCV004698052	uncertain significance	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing	Criteria applied: PM3,PM2_SUP,PP3
Natera, Inc.	RCV000233443	SCV001452309	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing