ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2495G>A (p.Arg832His)

gnomAD frequency: 0.00019  dbSNP: rs199875915
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130241 SCV000185084 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-03 criteria provided, single submitter clinical testing The p.R832H variant (also known as c.2495G>A), located in coding exon 16 of the ATM gene, results from a G to A substitution at nucleotide position 2495. The arginine at codon 832 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in 6/12503 unselected Japanese colorectal cancer patients and in 11/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec;:) and in one individual from a cohort of 52536 women diagnosed with invasive breast cancer (Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83). This amino acid position is poorly 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 RCV000168264 SCV000218935 likely benign Ataxia-telangiectasia syndrome 2024-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000483469 SCV000571820 uncertain significance not provided 2023-08-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27149842, 28652578, 30287823, 33471991, 20305132, 33588785, 32980694, 33309985)
Color Diagnostics, LLC DBA Color Health RCV000130241 SCV000911591 likely benign Hereditary cancer-predisposing syndrome 2021-10-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174859 SCV001338249 uncertain significance not specified 2020-02-07 criteria provided, single submitter clinical testing Variant summary: ATM c.2495G>A (p.Arg832His) results in a non-conservative amino acid change in 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 4.5e-05 in 291700 control chromosomes (gnomAD and literature.) This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (4.5e-05 vs 0.001), allowing no conclusion about variant significance. c.2495G>A has been reported in the literature in at least one individual affected with Breast Cancer without strong evidence for causality (Bernstein_2010). The variant has also been detected in healthy controls (e.g. Tiao_2017, Momozawa_2018). A large case-control study found no association for the variant with breast cancer (Momozawa_2018). These reports 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4 RCV000130241 SCV002532233 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-16 criteria provided, single submitter curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV004760391 SCV005373763 uncertain significance Hereditary breast ovarian cancer syndrome 2024-05-14 criteria provided, single submitter curation According to the ClinGen ACMG ATM v1.1.0 criteria we chose this criterion: BP4 (supporting benign): REVEL 0.023, SpliceAI 0.0
Natera, Inc. RCV000168264 SCV002077885 uncertain significance Ataxia-telangiectasia syndrome 2020-02-13 no assertion criteria provided clinical testing

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