ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7592T>C (p.Met2531Thr) (rs587781365)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129166 SCV000183899 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-28 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 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 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.7592T>C at the cDNA level, p.Met2531Thr (M2531T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Tavtigian et al. (2009) reported this variant in one breast cancer patient in a meta-analysis of case-control studies. This variant was also observed in an individual with early-onset colorectal cancer, co-occurring with an MLH1 truncating variant, as well as in one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps and two individuals with pancreatic cancer (Yurgelun 2015, Pearlman 2017, Chaffee 2018). ATM Met2531Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Met2531Thr is located within the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Met2531Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195721 SCV000254148 likely benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656762 SCV000344511 uncertain significance not provided 2016-08-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656762 SCV000840962 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129166 SCV000910932 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-08 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), pancreatic cancer (PMID: 28726808), and Lynch syndrome–associated cancer and/or polyps, although this individual was found to also have a co-occuring MLH1 germline mutation (PMID: 25980754, 27978560). 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 RCV001287892 SCV001474636 uncertain significance none 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.
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.

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