Submissions for variant NM_000051.4(ATM):c.2552A>G (p.Asp851Gly)

gnomAD frequency: 0.00001  dbSNP: rs748203812

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216103	SCV000277921	likely benign	Hereditary cancer-predisposing syndrome	2024-01-10	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	RCV000234621	SCV000282903	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 851 of the ATM protein (p.Asp851Gly). This variant is present in population databases (rs748203812, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 233529). 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.
GeneDx	RCV000478364	SCV000567605	uncertain significance	not provided	2024-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29596542, 34820595, 26976419, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000216103	SCV000913900	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 851 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. The variant has been observed in individuals affected with breast cancer (PMID 26976419) and pancreatic cancer (PMID: 34820595). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 2/251410 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.
Sema4, Sema4	RCV000216103	SCV002532277	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002485433	SCV002780410	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-12-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000234621	SCV002076209	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-17	no assertion criteria provided	clinical testing