Submissions for variant NM_000051.4(ATM):c.76G>C (p.Glu26Gln)

gnomAD frequency: 0.00001  dbSNP: rs730881361

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656754	SCV000209723	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Observed in individuals with chronic lymphocytic leukemia, endometrial, or breast cancer, as well as in control group in a breast cancer study (PMID: 28652578, 27443514, 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27443514, 35047863, 33471991, 28652578)
Ambry Genetics	RCV000215116	SCV000277995	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-26	criteria provided, single submitter	clinical testing	The p.E26Q variant (also known as c.76G>C), located in coding exon 2 of the ATM gene, results from a G to C substitution at nucleotide position 76. The glutamic acid at codon 26 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465732	SCV000546863	likely benign	Ataxia-telangiectasia syndrome	2024-12-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159711	SCV000602572	uncertain significance	not specified	2017-04-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215116	SCV000682431	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 26 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 33471991), endometrial cancer (PMID: 27443514), chronic lymphocytic leukemia (PMID: 28652578), as well as in unaffected controls (PMID: 33471991). This variant has not been identified 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	RCV000159711	SCV001362597	uncertain significance	not specified	2024-11-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.76G>C (p.Glu26Gln) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.76G>C has been reported in the literature in individuals affected with breast cancer (Dorling_2021), endometrial cancer (Ring_2016) and chronic lymphocytic leukemia (Tiao_2017), but it has also been reported in controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27443514, 28652578, 33471991). ClinVar contains an entry for this variant (Variation ID: 181944). Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV002288670	SCV002581670	uncertain significance	Familial cancer of breast	2022-07-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288670	SCV004205745	uncertain significance	Familial cancer of breast	2023-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000656754	SCV005621518	uncertain significance	not provided	2024-04-11	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) Computational tools predict that this variant is damaging.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656754	SCV005626338	uncertain significance	not provided	2024-10-31	criteria provided, single submitter	clinical testing	The ATM c.76G>C (p.Glu26Gln) variant has been reported in the published literature in individuals with endometrial cancer (PMID: 27443514 (2016)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), breast cancer (PMID: 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared)), and pancreatic cancer (PMID: 35047863 (2022)), as well as a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0000066 (1/152054 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000465732	SCV002090177	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-09	no assertion criteria provided	clinical testing