Submissions for variant NM_000051.4(ATM):c.8968G>A (p.Glu2990Lys)

gnomAD frequency: 0.00004  dbSNP: rs1800558

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212095	SCV000149181	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 25779943, 25980754, 28873162, 29368341, 28652578, 31970404, 33471991, 23532176, 29684080, 34326862, 35085662, 36845387, 32885271)
Ambry Genetics	RCV000115272	SCV000186450	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.E2990K variant (also known as c.8968G>A), located in coding exon 61 of the ATM gene, results from a G to A substitution at nucleotide position 8968. The glutamic acid at codon 2990 is replaced by lysine, an amino acid with similar properties. This alteration was seen in 1/150 unselected patients with recurrent or metastatic prostate cancer; this individual also had an alteration in BARD1 (Isaacsson Velho P et al. Prostate, 2018 04;78:401-407). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200530	SCV000254159	likely benign	Ataxia-telangiectasia syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115272	SCV000537525	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2990 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 an individual affected with Lynch syndrome-associated cancer and/or polyps, together with the pathogenic co-variant MSH6 c.3802-14_3809del (PMID: 25980754). This variant has also been reported in an individual affected with prostate cancer (PMID: 29368341) as well as in three women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 12/282800 chromosomes (11/10368 Ashkenazi Jewish chromosomes, 0.11%) 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.
Illumina Laboratory Services, Illumina	RCV000200530	SCV001264813	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). 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.
Sema4, Sema4	RCV000115272	SCV002530547	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-31	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271407	SCV002555955	likely benign	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8968G>A (p.Glu2990Lys) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.8968G>A has been reported in the literature in individuals affected with various cancers: Breast cancer (Dorling_2021, Lu_2015), Ovarian cancer (Lu_2015), Leukemia (Lu_2015), Astrocytoma (Muskens_2020), colon cancer (Yurgelun_2015), prostate cancer (Isaacsson Velho_2018), and gastrointestinal cancer (Bhai_2022). However, the variant was also found in 3/7325 European American women over the age of 70 with no history of cancer (FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA2 c.5946delT, p.Ser1982Argfs*22), providing supporting evidence for a benign role (Bhai_2022). 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: 25980754, 26689913, 29368341, 33471991, 31970404, 34326862). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six classified the variant as uncertain significance, and one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115272	SCV004014903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467036	SCV004209399	uncertain significance	Familial cancer of breast	2023-09-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358118	SCV001553771	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Glu2990Lys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.000397) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs1800558) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Color Genomics), and Clinvitae (3x as uncertain significance), databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0 databases. The variant was identified in control databases in 13 of 277140 chromosomes at a frequency of 0.000047 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 2 of 126628 chromosomes (freq: 0.000016), and Ashkenazi Jewish in 11 of 10150 chromosomes (freq: 0.001084), while the variant was not observed in the African, Other, Latino, East Asian, European (Finnish), and South Asian populations. The variant was identified with a co-occurring pathogenic BRCA1 variant (p.Gln1756ProfsX74), increasing the likelihood that the p.Glu2990Lys variant does not have clinical significance. The p.Glu2990Lys residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
GenomeConnect - Invitae Patient Insights Network	RCV003330438	SCV004037491	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant classified as Likely benign and reported on 02-25-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.