ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6820G>A (p.Ala2274Thr) (rs567060474)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122880 SCV000166138 likely benign Ataxia-telangiectasia syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000588200 SCV000209633 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.6820G>A at the cDNA level, p.Ala2274Thr (A2274T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). ATM Ala2274Thr was observed at an allele frequency of 0.02% (25/126,368) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. This variant has been observed in individuals with breast cancer, pancreatic cancer, rectal cancer, multiple myeloma, and chronic lymphocytic leukemia (Dork 2001, Scott 2002, Austen 2008, Broeks 2008, Tavtigian 2009, Skowronska 2011, Navrkalova 2013, Li 2015, Yang 2016, Pearlman 2017, Renault 2018), with some individuals also harboring a second ATM missense variant, Arg1575His. However, ATM Ala2274Thr showed incomplete segregation with breast cancer and was present in unaffected women in two families (Thorstenson 2003). Functional studies in support of a neutral classification demonstrated protein expression, kinase activity, ability to correct the radiosensitive phenotype of A-T cell lines, and levels of radiation-induced chromosome aberrations comparable to wild-type (Scott 2002, Barone 2009). Suggesting possible pathogenicity or unknown significance, other functional studies demonstrated reduction in protein expression and function (Stankovic 1999, Navrkalova 2013). Of note, Navrkalova et al. (2013) observed ATM Ala2274Thr and Arg1575His in the germline of an individual with CLL whose leukemic cells also harbored ATM Gln984Glu and an 11q chromosomal deletion as somatic alterations, and total ATM function was only reported from the leukemic cells analyzed. Based on currently available evidence, it is unclear whether ATM Ala2274Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159644 SCV000215124 likely benign Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001268972 SCV000694333 likely benign not specified 2020-11-24 criteria provided, single submitter clinical testing Variant summary: ATM c.6820G>A (p.Ala2274Thr) results in a non-conservative amino acid change located in the FAT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 271674 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. c.6820G>A has been reported in the literature in individuals with breast cancer (at least 5 patients), multiple myeloma (at least 1 patient) and at least 2 patients with chronic lymphocytic leukemia (example, Stankovic_1999, Dork_2001, Thorstenson_2003, Austen_2008, Broeks_2008, Tavtigian_2009, Skowronska_2011, Navrkalova_2012, Li_2016). In two reported HBOC families, this variant did not cosegregate with disease, suggesting a notion that it does not cause HBOC (Thorstenson_2003). However, the variants role as risk allele cannot be ruled out as the variant was found in a meta-analysis to be overrepresented in a patient population compared to a control population (Tavtigian_2009). These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as demonstrated by protein expression, kinase activity, and radiation-induced chromosome aberrations assays (Scott 2002, Barone 2009). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of actionable clinical and functional evidence outlined above, the variant was re-classified as likely benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000588200 SCV000705521 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing
Mendelics RCV000122880 SCV000838580 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000159644 SCV000910700 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122880 SCV001260750 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Division of Medical Genetics, University of Washington RCV001250436 SCV001424808 uncertain significance Familial cancer of breast 2019-06-27 criteria provided, single submitter clinical testing The c.6820G>A variant has been reported in individuals with breast cancer (Broeks 2008, Li 2016 ) but did not segregate with disease in two families with breast and ovarian cancer (Thorstenson 2003). The c.6820G>A variant has also been reported in the literature to co-occur with the ATM c.4724G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.6820 variant has a combined allele frequency of 0.00009 in the Broad Institute gnomAD Browser ( In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk.

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