ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile)

gnomAD frequency: 0.00003  dbSNP: rs779145081
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223476 SCV000273961 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-06 criteria provided, single submitter clinical testing The p.K2749I variant (also known as c.8246A>T), located in coding exon 55 of the ATM gene, results from an A to T substitution at nucleotide position 8246. The lysine at codon 2749 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in the germline of an individual with pancreatic ductal adenocarcinoma diagnosed at age 37 (Ohmoto A et al. Pancreas, 2016 08;45:1056-61). This alteration has also been detected in a Chinese patient with breast fibroadenoma (Xie SN et al. Cancer Med, 2019 05;8:2372-2379). This alteration was observed in with an allele frequency of 0.00468 in 7051 unselected female breast cancer patients and was observed with an allele frequency of 0.004 in 11241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0042 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina RCV000347894 SCV000367068 uncertain significance Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000347894 SCV000547049 uncertain significance Ataxia-telangiectasia syndrome 2022-10-28 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2749 of the ATM protein (p.Lys2749Ile). This variant is present in population databases (rs779145081, gnomAD 0.04%). This missense change has been observed in individual(s) with pancreatic cancer and breast cancer, as well as in unaffected controls (PMID: 26692440, 30287823, 30851086). ClinVar contains an entry for this variant (Variation ID: 230416). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Mendelics RCV000347894 SCV000838610 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000223476 SCV000911605 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-18 criteria provided, single submitter clinical testing This missense variant replaces lysine with isoleucine at codon 2749 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with pancreatic cancer (PMID: 26692440), leukemia (PMID: 27959900), breast fibroadenoma (PMID: 30851086), or breast cancer (PMID: 30851086). This variant has also been identified in 8/251016 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 30851086). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030605 SCV001193490 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 RCV001526927 SCV001737690 likely benign not specified 2021-05-22 criteria provided, single submitter clinical testing Variant summary: ATM c.8246A>T (p.Lys2749Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 345640 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8246A>T has been reported in the literature in individuals affected with Pancreatic ductal adenocarcinoma (Ohmoto_2016), breast cancer (Momozawa_2018), breast fibroadenomas (Xie_2019), colorectal cancer (Fujita_2020) and unaffected controls (Momozawa_2018, Fujita_2020). At-least one recent study evaluating population screening for hereditary colorectal cancer classified this variant as benign in the Japanese population (Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV003441794 SCV004169105 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer, breast cancer, prostate cancer, childhood-onset acute myeloid leukemia, and another with pancreatic cancer, but also in unaffected controls (Wang et al., 2015; Ohmoto et al., 2016; Momozawa et al., 2018; Fujita et al., 2020; So et al., 2022); Stracker TH et al. (2013) Front Genet. 4 :37 (PMID: 23532176); Wang X et al. (2015) Haematologica. 100 (10):e398-401 (PMID: 26022708); Ohmoto A et al. (2016) Pancreas. 45 (7):1056-61 (PMID: 26692440); Momozawa Y et al. (2018) Nat Commun. 9 (1):4083 (PMID: 30287823); Fujita M et al. (2020) Clin Gastroenterol Hepatol. (PMID: 33309985); So MK et al. (2022) Investig Clin Urol. 63 (3):294-300 (PMID: 35534218); This variant is associated with the following publications: (PMID: 26022708, 27959900, 27602761, 26692440, 23532176, 32566746, 35171259, 30851086, 30287823, 35534218, 36243179, 33309985)
Baylor Genetics RCV003469000 SCV004209416 uncertain significance Familial cancer of breast 2023-09-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003491969 SCV004239549 uncertain significance Breast and/or ovarian cancer 2023-04-20 criteria provided, single submitter clinical testing
Natera, Inc. RCV000347894 SCV001462606 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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