Submissions for variant NM_000051.4(ATM):c.1741T>G (p.Leu581Val)

gnomAD frequency: 0.00001  dbSNP: rs876659822

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219147	SCV000276688	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The p.L581V variant (also known as c.1741T>G), located in coding exon 10 of the ATM gene, results from a T to G substitution at nucleotide position 1741. The leucine at codon 581 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in several studies, identified in both cancer cases and unaffected controls (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9; Dorling et al. N Engl J Med 2021 02;384:428-439; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Wardell CP et al. J Hepatol, 2018 May;68:959-969). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000484735	SCV000572430	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25428177, 33544757)
Color Diagnostics, LLC DBA Color Health	RCV000219147	SCV000681995	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 581 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251044 chromosomes 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	RCV000627927	SCV000748812	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 581 of the ATM protein (p.Leu581Val). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 30287823, 32980694). ClinVar contains an entry for this variant (Variation ID: 232530). 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 tolerated. 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030519	SCV001193467	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174637	SCV001337846	uncertain significance	not specified	2024-04-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1741T>G (p.Leu581Val) results in a 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 1.2e-05 in 251044 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1741T>G has been reported in the literature in individuals affected with Breast Cancer, Colon Cancer and in controls as well (example, Dorling_2021, Fujita_2022, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 33471991, 33309985, 30287823).ClinVar contains an entry for this variant (Variation ID: 232530). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000219147	SCV002531098	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	curation
Athena Diagnostics	RCV000484735	SCV002771690	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484735	SCV004220016	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (3/18392 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in healthy individuals (PMIDs: 29059438 (2017), 30287823 (2018), 32980694 (2020), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/ATM), 33309985 (2022)) as well as individuals with breast cancer (PMIDs: 30287823 (2018), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/ATM)), pancreatic cancer (PMID: 32980694 (2020)), and colorectal cancer (PMID: 33309985 (2022)). Functional studies report the variant does not impact protein function (PMID: 29059438 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000627927	SCV001461013	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing