ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs567060474
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122880 SCV000166138 likely benign Ataxia-telangiectasia syndrome 2024-01-29 criteria provided, single submitter clinical testing
GeneDx RCV000588200 SCV000209633 uncertain significance not provided 2022-12-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: most show no or minimal impact on protein expression, kinase activity, ability to correct the radiosensitive phenotype of A-T cell lines, and levels of radiation-induced chromosome aberrations (Stankovic et al., 1999; Scott et al., 2002; Barone et al., 2009); Observed in individuals with ATM-related and other cancers, but also in unaffected controls (Dork et al., 2001; Scott et al., 2002; Austen et al., 2008; Broeks et al., 2008; Tavtigian et al., 2009; Skowronska et al., 2011; Navrkalova et al., 2013; Li et al., 2016; Yang et al., 2016; Pearlman et al., 2017; Tiao et al., 2017; Hauke et al., 2018; Renault et al., 2018; elebi and Bolat, 2022); This variant is associated with the following publications: (PMID: 23585524, 10023947, 26787654, 16652348, 11606401, 19781682, 18573109, 21933854, 17393301, 12810666, 22529920, 15279808, 11805335, 19431188, 26534844, 27449771, 21787400, 27978560, 29665859, 28652578, 29522266, 33128190, 30613976, 23532176, elebi2022[article])
Ambry Genetics RCV000159644 SCV000215124 likely benign Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001268972 SCV000694333 likely benign not specified 2023-11-20 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 estimated 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). The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 19431188, 17393301, 11606401, 26534844, 23585524, 27978560, 11805335, 21933854, 10023947, 19781682, 12810666, 28652578, 27449771). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=3, VUS, n=6, Pathogenic, n=1). 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 classified as likely benign.
Eurofins Ntd Llc (ga) 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 Diagnostics, LLC DBA Color Health RCV000159644 SCV000910700 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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 (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk.
Athena Diagnostics Inc RCV000588200 SCV002771712 uncertain significance not provided 2023-01-16 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188, 11805335)
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV001824286 SCV002074128 pathogenic Tip-toe gait 2021-10-21 flagged submission clinical testing

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