Submissions for variant NM_000051.4(ATM):c.5489T>C (p.Met1830Thr)

gnomAD frequency: 0.00021  dbSNP: rs145812395

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212029	SCV000149122	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in an individual with non-neoplastic hematologic disease (PMID: 36315919); This variant is associated with the following publications: (PMID: 20177704, 36315919, 36117189)
Ambry Genetics	RCV000115213	SCV000217197	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.M1830T variant (also known as c.5489T>C), located in coding exon 35 of the ATM gene, results from a T to C substitution at nucleotide position 5489. The methionine at codon 1830 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167908	SCV000218556	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1830 of the ATM protein (p.Met1830Thr). This variant is present in population databases (rs145812395, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127408). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000115213	SCV000682267	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1830 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 not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 10/282110 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001281031	SCV001468447	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-11	criteria provided, single submitter	clinical testing	ATM NM_000051.3 exon 36 p.Met1830Thr (c.5489T>C): This variant has not been reported in the literature but is present in 0.04% (10/24952) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108173749-T-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:127408). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212029	SCV001474098	uncertain significance	not provided	2020-03-20	criteria provided, single submitter	clinical testing	The ATM c.5489T>C; p.Met1830Thr variant (rs145812395), to our knowledge, is not reported in the medical literature but is reported in the ClinVar database (Variation ID: 127408). This variant is found in the general population with an overall allele frequency of 0.004% (10/282110 alleles) in the Genome Aggregation Database. The methionine at codon 1830 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804843	SCV002050842	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5489T>C (p.Met1830Thr) results in a non-conservative amino acid change in 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 1.6e-05 in 250720 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.5489T>C has not been reported in the literature in individuals affected with Breast Cancer and 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: 36117189, 36315919). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000115213	SCV002528497	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004549558	SCV004119330	uncertain significance	ATM-related disorder	2023-10-30	criteria provided, single submitter	clinical testing	The ATM c.5489T>C variant is predicted to result in the amino acid substitution p.Met1830Thr. This variant has been reported in an polymorphism in a breast cancer cohort study (Table 2, Bozhanov et al. 2010. PubMed ID: 20177704). It is reported in 0.040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108173749-T-C) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127408/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460806	SCV004208396	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000115213	SCV004805213	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003460806	SCV005084536	likely benign	Familial cancer of breast	2024-05-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000167908	SCV001452317	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing