Submissions for variant NM_000051.4(ATM):c.6503C>T (p.Ser2168Leu)

gnomAD frequency: 0.00008  dbSNP: rs200431631

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206774	SCV000261140	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216900	SCV000274735	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	The p.S2168L variant (also known as c.6503C>T), located in coding exon 44 of the ATM gene, results from a C to T substitution at nucleotide position 6503. The serine at codon 2168 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in numerous cancer cohorts as well as unaffected control groups across studies (Decker B et al. J. Med. Genet. 2017;54(11):732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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). It has also been identified in individuals diagnosed with breast cancer (Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Fostira F et al. Breast Cancer Res. Treat. 2018;169(1):105-113; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554). This alteration has also been reported in conjunction with an ATM frameshift mutation in a patient with unexplained ataxia; phase was not reported (Cheng HL et al. Transl Neurodegener, 2021 Oct;10:40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000216900	SCV000537533	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2168 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: 23555315, 28580595, 28779002, 29335925, 30287823, 33471991) and in unaffected individuals (PMID: 30287823, 32658311, 33471991). This variant has also been identified in 24/282838 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.
GeneDx	RCV000588892	SCV000568996	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Observed in individuals with breast, pancreatic or colon cancer, and also in unaffected controls (Haiman et al., 2013; Decker et al., 2017; Fostira et al., 2018; Momozawa et al., 2018; Xie et al., 2018; Yehia et al., 2018; Ackay et al., 2020; Kwong et al., 2020; Mizukami et al., 2020); Observed with a truncating ATM variant in a child with ataxia and dysarthria, and it is not known whether the variants occurred on the same (in cis) allele or on opposite (in trans) alleles (Cheng et al., 2021); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 31248605, 29684080, 32068069, 32658311, 28580595, 23555315, 28779002, 29335925, 30287823, 36300887, 32980694, 23532176, 34663476)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001268980	SCV000694325	uncertain significance	not specified	2021-06-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6503C>T (p.Ser2168Leu) results in a non-conservative amino acid change located in the PIK-related kinase domain 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 0.00013 in 299890 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The frequency in the East Asian subpopulation is close to, but does not exceed, the estimated maximum allele frequency expected for a pathogenic variant in ATM causing Breast Cancer (0.00082 vs 0.001), allowing no conclusion about variant significance. c.6503C>T has been reported in the literature in individuals affected with Breast and Prostate Cancers (e.g.Haiman_2013, Xie_2018, Fostira_2018, Momozawa_2018, Wei_2019, Kwong_2020). In one large case-control study within the Japanese population, this variant was found in both cases and controls and was not shown to be associated with breast cancer (OR=0.4, p=0.222; Momozawa_2018) . These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5682C>G, p.Y1894X; Wei_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000206774	SCV000838574	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763709	SCV000894589	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Department of Neurology, Xijing Hospital, Fourth Military Medical University	RCV000206774	SCV002553227	uncertain significance	Ataxia-telangiectasia syndrome	2022-03-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588892	SCV002774773	uncertain significance	not provided	2022-05-17	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000216900	SCV005045427	benign	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567472	SCV005057147	uncertain significance	Familial cancer of breast	2023-12-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000206774	SCV001457419	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing