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

gnomAD frequency: 0.00009  dbSNP: rs567060474

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122880	SCV000166138	likely benign	Ataxia-telangiectasia syndrome	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000588200	SCV000209633	uncertain significance	not provided	2023-12-17	criteria provided, single submitter	clinical testing	Observed in individuals with ATM-related and other cancers, but also in unaffected controls (PMID: 11606401, 11805335, 18573109, 17393301, 19781682, 21933854, 23585524, 26689913, 26534844, 27449771, 28779002, 27978560, 28652578, 29522266, 29665859, 35264596); 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 (PMID: 10023947, 11805335, 19431188); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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, 36029002, 28779002, 26689913, elebi2022[article], 35264596, 23532176, 34262154, 34326862, 35534704)
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: seen in unaffected individuals, 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	RCV004562279	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	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)
Myriad Genetics, Inc.	RCV001250436	SCV005084815	likely benign	Familial cancer of breast	2024-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760385	SCV005373747	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	curation	According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: BS3 (medium benign): 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) Paper_Andreassen: et al unpublished BS3_Str
Mayo Clinic Laboratories, Mayo Clinic	RCV000588200	SCV005412471	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	BS3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588200	SCV005626072	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing
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	Gait disorder