Submissions for variant NM_000051.4(ATM):c.295A>G (p.Ser99Gly)

gnomAD frequency: 0.00019  dbSNP: rs137882485

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588846	SCV000149078	uncertain significance	not provided	2022-02-07	criteria provided, single submitter	clinical testing	Identified in patients with breast cancer, prostate cancer, or chronic lymphocytic leukemia, but also in healthy controls (Lahdesmaki 2004, Tavtigian 2009, Tung 2015, Decker 2017, Tiao 2017, Hauke 2018, Girard 2019, Karlsson 2021); 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: 30303537, 19781682, 14754616, 26787654, 28873162, 28652578, 28779002, 25186627, 29522266, 29684080, 31552911, 33436325)
Ambry Genetics	RCV000115169	SCV000183799	likely benign	Hereditary cancer-predisposing syndrome	2021-01-29	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196996	SCV000254077	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515313	SCV000611354	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855626	SCV000694242	likely benign	not specified	2024-09-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.295A>G (p.Ser99Gly) 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. Three 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 1638634 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00011 vs 0.004), allowing no conclusion about variant significance. c.295A>G has been reported in the literature in individuals affected with Breast Cancer (examples: Tavtigian_2009, Tung_2015, Girard_2019), but also in healthy controls (examples: Tiao_2017, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variants have been observed in our laboratory (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161fs; MSH2 c.942+3A>T), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 25186627, 14754616, 26787654, 28873162, 28652578, 30303537, 33471991, 30883245, 34262154, 35309086, 35264596, 33436325, 31206626). These report(s) do not provide unequivocal conclusions about association of the variant with ATM-related conditions. 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: 30883245, 34262154, 33471991, 35309086, 30303537, 35264596, 33436325, 14754616, 28873162, 19781682, 28652578, 25186627, 31206626, 26787654). ClinVar contains an entry for this variant (Variation ID: 127364). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000196996	SCV000790963	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000196996	SCV000838467	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115169	SCV000902647	likely benign	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196996	SCV001260303	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV001293035	SCV001481547	uncertain significance	Familial cancer of breast	2020-07-01	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000115169	SCV002535234	likely benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000588846	SCV004131392	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ATM: PM2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588846	SCV004220902	likely benign	not provided	2018-12-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001293035	SCV005083940	likely benign	Familial cancer of breast	2024-04-18	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].
Mayo Clinic Laboratories, Mayo Clinic	RCV000588846	SCV005412446	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	BS1
True Health Diagnostics	RCV000115169	SCV000787857	uncertain significance	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588846	SCV001554155	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Ser99Gly variant was identified in 3 of 7786 proband chromosomes (frequency: 0.0004) from individuals or families with B-chronic lymphocytic leukemia or breast cancer and was not identified in 6732 control chromosomes from healthy individuals (Lähdesmäki 2004, Tavtigian 2009, Young 2016). The variant was also identified in dbSNP (ID: rs137882485) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx, and five other submitters). The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 71 of 276750 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10144 chromosomes (freq: 0.004), Other in 5 of 6464 chromosomes (freq: 0.0008), Latino in 23 of 34384 chromosomes (freq: 0.0007), and European in 4 of 126388 chromosomes (freq: 0.00003); it was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Ser99 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One study suggested a non-pathogenic role for this variant (Lähdesmäki 2004). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000855626	SCV003839192	uncertain significance	not specified	2022-12-14	no assertion criteria provided	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.295A>G, in exon 4 that results in an amino acid change, p.Ser99Gly. This sequence change has been described in the gnomAD database with a frequency of 0.38% in the Ashkenazi Jewish subpopulation (dbSNP rs137882485). The p.Ser99Gly change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser99Gly substitution. The Ser99Gly change has been identified in individuals with breast cancer, prostate cancer, and chronic lymphocytic leukemia (PMID: 19781682, 33436325, 28652578). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser99Gly change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV004739389	SCV005364050	likely benign	ATM-related disorder	2024-09-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).