ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7502A>G (p.Asn2501Ser)

gnomAD frequency: 0.00003  dbSNP: rs531617441
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222504 SCV000276626 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing The p.N2501S variant (also known as c.7502A>G), located in coding exon 49 of the ATM gene, results from an A to G substitution at nucleotide position 7502. The asparagine at codon 2501 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in 0/53 unselected male breast cancer patients and 1/12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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 RCV000233636 SCV000283057 likely benign Ataxia-telangiectasia syndrome 2021-12-07 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000233636 SCV000367067 uncertain significance Ataxia-telangiectasia syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000486420 SCV000569199 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.7502A>G at the cDNA level, p.Asn2501Ser (N2501S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Asn2501Ser was observed at an allele frequency of 0.13% (39/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). ATM Asn2501Ser is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asn2501Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000222504 SCV000682418 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-02 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 2501 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 absent in affected individuals and in at least one unaffected individual in a breast cancer risk case-control study (PMID: 30287823). This variant has been identified in 44/282496 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.
Baylor Genetics RCV000233636 SCV000807599 uncertain significance Ataxia-telangiectasia syndrome 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it in trans with a known deleterious mutation in a 10-year-old male with global delays, myopathy, epilepsy, generalize muscle weakness, and abnormal brain MRI. Heterozygotes are expected to be asymptomatic carriers.
Fulgent Genetics,Fulgent Genetics RCV000764945 SCV000896117 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000233636 SCV001781396 uncertain significance Ataxia-telangiectasia syndrome 2021-07-14 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000486420 SCV001879582 uncertain significance not provided 2021-05-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001818535 SCV002064843 uncertain significance not specified 2020-10-12 criteria provided, single submitter clinical testing DNA sequence analysis of the ATM gene demonstrated a sequence change, c.7502A>G, in exon 50 that results in an amino acid change, p.Asn2501Ser. This sequence change does not appear to have been previously described in patients with ATM-related disorders and has been described in the gnomAD database with a frequency of 0.12% in the South Asian population (dbSNP rs531617441). The p.Asn2501Ser 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.Asn2501Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn2501Ser change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818535 SCV002556088 likely benign not specified 2022-06-23 criteria provided, single submitter clinical testing Variant summary: ATM c.7502A>G (p.Asn2501Ser) results in a conservative amino acid change located in the PIK-related kinase domain (IPR014009) 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 0.00017 in 251096 control chromosomes, predominantly at a frequency of 0.0012 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.7502A>G has been reported in the literature as a VUS in settings of multigene panel testing in unaffected Japanese male control individuals but not in cases affected with Breast Cancer (example, Momozawa_2018) and also in cases with breast cancer and unaffected controls in another study (example, Dorling_2021). These report(s) 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=10; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc. RCV000233636 SCV001458470 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000486420 SCV001552991 uncertain significance not provided no assertion criteria provided clinical testing The ATM p.Asn2501Ser variant was identified in the literature in 12490 male controls with frequency 0.0001 and was not identified in 11241 female controls and 53 male and 7051 female breast cancer cases (Momozawa 2018). The variant was also identified in dbSNP (ID: rs531617441) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and five other submitters), and in LOVD 3.0 (1x). The variant was identified in control databases in 46 of 276956 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24024 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 3 of 34414 chromosomes (freq: 0.00009), European in 2 of 126472 chromosomes (freq: 0.00002), and South Asian in 39 of 30782 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Asn2501 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. 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.

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