Submissions for variant NM_000051.4(ATM):c.2564T>C (p.Met855Thr)

gnomAD frequency: 0.00001  dbSNP: rs587779824

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115158	SCV000149067	uncertain significance	not provided	2019-08-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000565873	SCV000672635	likely benign	Hereditary cancer-predisposing syndrome	2024-03-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698456	SCV000827121	uncertain significance	Ataxia-telangiectasia syndrome	2021-12-10	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 855 of the ATM protein (p.Met855Thr). This variant is present in population databases (rs587779824, gnomAD 0.002%). 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: 127353). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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	RCV000565873	SCV001348269	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 855 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 2/251430 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.
MGZ Medical Genetics Center	RCV002288587	SCV002579325	uncertain significance	Familial cancer of breast	2022-05-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000698456	SCV002076231	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-22	no assertion criteria provided	clinical testing