Submissions for variant NM_000051.4(ATM):c.7592T>C (p.Met2531Thr)

gnomAD frequency: 0.00004  dbSNP: rs587781365

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129166	SCV000183899	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The p.M2531T variant (also known as c.7592T>C), located in coding exon 50 of the ATM gene, results from a T to C substitution at nucleotide position 7592. The methionine at codon 2531 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in 1/ 26 indigenous Russian breast cancer patients (Gervas P et al. Mol. Biol. Rep., 2019 Oct;46:5537-5541). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration co-occurred with an MLH1 pathogenic mutation in a patient with MMR-deficient rectosigmoid junction cancer diagnosed at age 34 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This variant was reported in 4/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000656762	SCV000209644	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, pancreatic and other cancers, but also in unaffected controls (Tavtigian et al., 2009; Yurgelun et al., 2015; Pearlman et al., 2017; Tiao et al., 2017; Chaffee et al., 2018; Hauke et al., 2018; Gervas et al., 2019; Akcay et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 21787400, 19781682, 27978560, 28726808, 28652578, 29522266, 31273614, 32658311, 23532176, 36577833, 33471991, 34326862, 33750258)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195721	SCV000254148	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000656762	SCV000344511	uncertain significance	not provided	2016-08-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000656762	SCV000840962	uncertain significance	not provided	2021-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129166	SCV000910932	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 2531 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. This variant has been reported in individuals affected with breast cancer (PMID: 19781682, 20305132, 31273614) and pancreatic cancer (PMID: 28726808). This variant has also been reported with a co-occuring MLH1 germline mutation in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 27978560). In a large case-control study, this variant was reported in 4/60462 breast cancer cases and 3/53458 controls (OR=1.179, 95%CI 0.264 to 5.268, p-value=1; PMID: 33471991). This variant has also been identified in 12/282448 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192416	SCV001360527	likely benign	not specified	2021-01-09	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7592T>C (p.Met2531Thr) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251246 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is close to that expected for a pathogenic variant in ATM causing Breast Cancer (9.7e-05 vs 0.001), supporting a neutral impact. c.7592T>C has been reported in the literature in individuals affected with a variety of cancers (example, Tavtigian_2009, Yurgelun_2015, Chaffee_2018, Gervas_2019, Pearlman_2017, Ackay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. At-least two reports of a co-occurrence with another pathogenic variant have been reported (MLH1 c.1279C>T, p.Gln427*, Pearlman_2017 and Yurgelun_2015). One of these individuals with a co-occurring MLH1 pathogenic variant was reported to have colon cancer at rectosigmoid junction, MMR deficient tumor status, a strong family history of cancer, and met the NCCN criteria for a hereditary cancer syndrome consistent with the MLH1 gene (Pearlman_2017). These observations provide additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1, VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of concrete evidence supporting an actionable outcome spanning over a decade of literature evidence as outlined above, the variant was re-classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656762	SCV001474636	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	The ATM c.7592T>C; p.Met2531Thr variant (rs587781365) is reported in the literature in individuals affected with breast, pancreatic, colorectal cancer, or suspected Lynch syndrome (Chaffee 2018, Goldgar 2011, Hauke 2018, Tavtigian 2009, Yurgelun 2015), including one individual with colorectal cancer who also carries a pathogenic MLH1 variant (Pearlman 2017). This variant is reported in ClinVar (Variation ID: 140910), and is found in the non-Finnish European population with an allele frequency of 0.0093% (12/129062 alleles) in the Genome Aggregation Database. The methionine at codon 2531 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the limited clinical information and lack of functional data, the significance of the p.Met2531Thr variant is uncertain at this time. References: Chaffee KG et al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet Med. 2018 Jan;20(1):119-127. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Hauke J et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med. 2018 Apr;7(4):1349-1358. Pearlman et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. Tavtigian et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-46. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
Sema4, Sema4	RCV000129166	SCV002538104	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004551240	SCV004114402	uncertain significance	ATM-related disorder	2023-07-12	criteria provided, single submitter	clinical testing	The ATM c.7592T>C variant is predicted to result in the amino acid substitution p.Met2531Thr. This variant has been reported in an individual tested for Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), as a variant of uncertain significance in patients with breast cancer and pancreatic ductal adenocarcinoma (Table S2, Chaffee et al. 2018. PubMed ID: 28726808; Hauke et al. 2018. PubMed ID: 29522266; Table 1, Gervas et al. 2019. PubMed ID: 31273614), in control group in breast cancer study (Table S6, Akcay et al. 2020. PubMed ID: 32658311) and in patients with colorectal cancer and with ALL where pathogenic causative variants in other genes were detected (Pearlman et al. 2017. PubMed ID: 27978560; Hrabovsky et al. 2021. PubMed ID: 33750258). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108202247-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460890	SCV004216222	uncertain significance	Familial cancer of breast	2021-07-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656762	SCV004222181	uncertain significance	not provided	2021-11-24	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 34326862 (2021), 33471991 (2021), 31273614 (2019), 29522266 (2018), 19781682 (2009)), pancreatic cancer (PMID: 28726808 (2018)), and leukemia (PMID: 33750258 (2021)). This variant has also been observed in healthy control individuals (PMID: 32658311 (2021), 33471991 (2021), see LOVD (http://databases.lovd.nl/shared/), and in individuals with colorectal cancer/suspected Lynch syndrome who carried a pathogenic variant in the MLH1 gene (PMIDs: 27978560 (2016), 25980754 (2015)). The frequency of this variant in the general population, 0.000093 (12/129062 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656762	SCV005412476	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656762	SCV001551773	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Met2531Thr variant was identified in 5 of 9122 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome, breast, pancreatic or early onset CRC and was not identified in 4490 control chromosomes from healthy individuals (Yurgelun 2015, Tavtigian 2009, Pearlman 2017, Chaffee 2018). In these studies, the variant co-occurred with a pathogenic MLH1 variant (c.1279C>T/p.Gln427*) in two of the probands with Lynch/early onset CRC. The variant was also identified in dbSNP (ID: rs587781365) as “With Uncertain significance allele”, and ClinVar (classified uncertain significance; submitters: Invitae, Ambry Genetics, GeneDx and 3 other laboratories). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 10 of 276888 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 10 of 126660 chromosomes (freq: 0.00008) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Met2531 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.