Submissions for variant NM_000051.4(ATM):c.4394T>C (p.Leu1465Pro)

dbSNP: rs730881391

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003467242	SCV004565386	likely pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (</=0.001%) for PM2_Supporting, meeting this criterion. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 9463314, 10234507, 26896183). The computational predictor, Revel (Score: 0.802), predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PM2_supporting, PM3_strong, PP3).
GeneDx	RCV000159765	SCV000209785	likely pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced kinase activity (PMID: 19431188); Identified in individuals with breast or prostate cancer and segregates with breast cancer in at least one family (PMID: 32853339, 33436325, 37232349); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27304073, 22529920, 26681312, 29308099, 29922827, 10234507, 26896183, 27153395, 33436325, 32853339, 37232349, 19431188)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206187	SCV000261048	uncertain significance	Ataxia-telangiectasia syndrome	2022-04-28	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects ATM function (PMID: 10234507, 19431188). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1465 of the ATM protein (p.Leu1465Pro). This variant is present in population databases (rs730881391, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia, esophageal cancer, gastric cancer, and/or prostate cancer (PMID: 10234507, 26681312, 26896183, 32853339, 33436325). 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: 181996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function.
Ambry Genetics	RCV000220574	SCV000274029	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.L1465P variant (also known as c.4394T>C), located in coding exon 28 of the ATM gene, results from a T to C substitution at nucleotide position 4394. The leucine at codon 1465 is replaced by proline, an amino acid with very few similar properties. This variant has been reported in the literature in a compound heterozygous state in an Irish individual with Ataxia-Telangiectasia (A-T). Functional analysis indicated low levels of ATM expression (1%) suggesting that this alteration likely changes the secondary structure of the protein as the proline substitution is located in the middle of a predicted &alpha;-helix from amino acids 1460 to 1476 (Izatt L et al. Eur. J. Hum. Genet. 1999 Apr; 7(3):310-20). An additional report suggests this alteration results in reduced kinase activity. Authors note that 8 of the 10 ATM variants in this study with reduced kinase activity were identified in A-T patients with a milder A-T phenotype, but do not specify which 8 (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel. This individual had a personal history of esophageal and gastric cancers (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This variant was reported in 10/5560 prostate cancer cases and in 2/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol. 2021 Aug;4:570-579). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability; however, the impact on protein function is not clear (Ambry internal data; Bareti D et al. Sci Adv. 2017 May;3(5):e1700933). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206187	SCV000694280	likely pathogenic	Ataxia-telangiectasia syndrome	2015-10-30	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 4/4 in silico tools predict damaging outcome for this substitution. Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM variant (0.4%). The variant was reported in one A-T patient (Izatt_EJHG_1999) who was compound heterozygote for the variant of interest and a potentially deleterious frameshift/truncating variant 1355delC; p.Thr452Asnfs indicating the variant to have a role in A-T pathology. Furthermore, Izatt_EJHG_1999 showed the variant to result in low level of ATM expression indicating that the L1465P missense mutation may lead to instability of the protein. Additionally, Barone_Hum Mutat_2009 reported the L1465P ATM variant to have reduced kinase activity toward its downstream targets providing an independent support for the pathogenicity of the variant. A clinical laboratory classifies variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate) and HGMD lists variant with a classification of Disease Mutation. Considering all evidence, the variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000206187	SCV002024405	likely pathogenic	Ataxia-telangiectasia syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467242	SCV004209466	likely pathogenic	Familial cancer of breast	2023-09-12	criteria provided, single submitter	clinical testing