Submissions for variant NM_000051.4(ATM):c.131A>G (p.Asp44Gly)

gnomAD frequency: 0.00013  dbSNP: rs150143957

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166071	SCV000216834	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.D44G variant (also known as c.131A>G), located in coding exon 2 of the ATM gene, results from an A to G substitution at nucleotide position 131. The aspartic acid at codon 44 is replaced by glycine, an amino acid with similar properties. In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in eight women (Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). This alteration has been identified in multiple individuals diagnosed with breast cancer (Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Tung N et al. Cancer, 2015 Jan;121:25-33; Uyisenga JP et al. Mol Genet Genomic Med, 2020 11;8:e1500; Eygelaar D et al. Sci Rep, 2022 Jan;12:802; McDonald JT et al. PLoS One, 2022 Oct;17:e0273835). This alteration has also been identified in multiple individuals diagnosed with prostate cancer (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Gheybi K et al. J Natl Compr Canc Netw, 2023 Mar;21:289-296.e3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000197254	SCV000254057	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 44 of the ATM protein (p.Asp44Gly). This variant is present in population databases (rs150143957, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 31871109, 35039564, 36315513). ClinVar contains an entry for this variant (Variation ID: 186471). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
GeneDx	RCV000590355	SCV000278807	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast or prostate cancer (Haiman et al., 2013; Tung et al., 2015; Uyisenga et al., 2020; Eygelaar et al., 2022; McDonald et al., 2022; Gheybi et al., 2023); This variant is associated with the following publications: (PMID: 25186627, 32959997, 35039564, 31871109, 23555315, 36898365, 36315513, 32832836)
Color Diagnostics, LLC DBA Color Health	RCV000166071	SCV000681966	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 44 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31871109, 32959997, 33471991, 35039564, 36315513) and prostate cancer (PMID: 36898365). This variant has been identified in 11/282598 chromosomes 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	RCV001255212	SCV000694177	uncertain significance	not specified	2020-08-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.131A>G (p.Asp44Gly) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) 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 0.00019 in 143258 control chromosomes, predominantly at a frequency of 0.0006 within the African or African-American subpopulation in the gnomAD database (v3 genomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.0006 vs 0.001), allowing no conclusion about variant significance. In addition, this variant has been reported in 2/2559 African American women and 1/7325 European American women, who were older than age 70 and cancer free (in the FLOSSIES database). The variant, c.131A>G, has also been reported in the literature in African- or African-American individuals affected with Breast Cancer (Haiman_2013, Tung_2015, Adedokun_2020). These reports however 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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000197254	SCV000797741	uncertain significance	Ataxia-telangiectasia syndrome	2018-02-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000197254	SCV001138425	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001255212	SCV002069332	uncertain significance	not specified	2018-07-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166071	SCV002530276	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000197254	SCV003827462	uncertain significance	Ataxia-telangiectasia syndrome	2021-12-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474873	SCV004203749	uncertain significance	Familial cancer of breast	2024-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003474873	SCV005083842	likely benign	Familial cancer of breast	2024-04-17	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].
Natera, Inc.	RCV000197254	SCV002088210	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-22	no assertion criteria provided	clinical testing