ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.295A>G (p.Ser99Gly) (rs137882485)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588846 SCV000149078 uncertain significance not provided 2021-06-17 criteria provided, single submitter clinical testing Identified in patients with breast cancer or chronic lymphocytic leukemia, but also in healthy controls (Lahdesmaki 2004, Tavtigian 2009, Tung 2015, Decker 2017, Tiao 2017, Hauke 2018, Girard 2019); 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: 31552911, 29684080, 29522266, 25186627, 28779002, 28652578, 28873162, 26787654, 14754616, 19781682, 30303537)
Ambry Genetics RCV000115169 SCV000183799 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing The p.S99G variant (also known as c.295A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 295. The serine at codon 99 is replaced by glycine, an amino acid with similar properties. This alteration was detected in 1/4112 breast cancer cases and 0/2399 healthy controls across multiple independent studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was also reported in 0.4% of 516 CLL cases and 0.02% of 8920 healthy controls (Tiao G et al. Leukemia. 2017 10;31:2244-2247). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000196996 SCV000254077 benign Ataxia-telangiectasia syndrome 2020-12-07 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 2021-03-07 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 0.00027 in 275970 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00027 vs 0.001), 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 variant(s) have been observed in our laboratory (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161fs; MSH2 c.942+3A>T), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=1; benign, n=1; VUS, n=7). Based on the evidence outlined above, the variant was re-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 Health, Inc RCV000115169 SCV000902647 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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].
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.