Submissions for variant NM_000051.4(ATM):c.2539A>G (p.Met847Val)

dbSNP: rs587779823

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115157	SCV000149066	uncertain significance	not provided	2013-09-27	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2539A>G at the cDNA level and p.Met847Val (M847V) at the protein level, resulting in the change of a Methionine (ATG) to a Valine (GTG) at amino acid 847 in exon 11. This variant is a conservative substitution of one neutral, non-polar amino acid for another and alters a position that is not well conserved throughout evolution. In silico analyses predict ATM Met847Val to have a benign effect on the protein structure/function. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Given the available evidence, it is not possible to conclude whether this variant is pathogenic or benign, and we therefore consider it to have unknown significance. The variant is found in BR-OV-HEREDIC panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689269	SCV000816911	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 valine, which is neutral and non-polar, at codon 847 of the ATM protein (p.Met847Val). This variant is present in population databases (rs587779823, gnomAD 0.003%). 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: 127352). 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.
Ambry Genetics	RCV001015804	SCV001176679	likely benign	Hereditary cancer-predisposing syndrome	2025-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV004566994	SCV005057126	uncertain significance	Familial cancer of breast	2023-12-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005364991	SCV005919539	uncertain significance	ATM-related cancer predisposition	2023-11-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000689269	SCV002080302	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-21	no assertion criteria provided	clinical testing