Submissions for variant NM_000051.4(ATM):c.1814A>G (p.His605Arg)

gnomAD frequency: 0.00001  dbSNP: rs771877351

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236945	SCV000293733	uncertain significance	not provided	2023-10-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Tommiska et al., 2006; Bernstein et al., 2010).; 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: 16914028, 20305132)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628205	SCV000749099	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 605 of the ATM protein (p.His605Arg). This variant is present in population databases (rs771877351, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 16914028, 20305132). ClinVar contains an entry for this variant (Variation ID: 246258). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779798	SCV000916602	uncertain significance	not specified	2018-10-22	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1814A>G (p.His605Arg) 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 1.8e-05 in 276728 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1814A>G, has been reported in the literature in individuals affected with breast cancer (Tommiska_2006, Bernstein_2010), including a family where it did not segregate with disease in 3 other individuals. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001013284	SCV001173852	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The c.1814A>G (p.H605R) alteration is located in exon 12 (coding exon 11) of the ATM gene. This alteration results from a A to G substitution at nucleotide position 1814, causing the histidine (H) at amino acid position 605 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000779798	SCV004027165	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001013284	SCV004359777	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 605 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 individuals affected with breast cancer (PMID: 16914028, 20305132). However, in one study, this variant was not found in first- and second-degree relatives affected with breast cancer (PMID: 16914028). This variant has been identified in 4/281872 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.
Natera, Inc.	RCV000628205	SCV002083901	uncertain significance	Ataxia-telangiectasia syndrome	2021-09-28	no assertion criteria provided	clinical testing