Submissions for variant NM_000051.4(ATM):c.1648A>G (p.Ile550Val)

gnomAD frequency: 0.00001  dbSNP: rs202144949

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165266	SCV000215982	likely benign	Hereditary cancer-predisposing syndrome	2018-11-27	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.
GeneDx	RCV001721071	SCV000512139	likely benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19781682, 11606401, 26336887)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470788	SCV000546901	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 550 of the ATM protein (p.Ile550Val). This variant is present in population databases (rs202144949, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 11606401). ClinVar contains an entry for this variant (Variation ID: 185780). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV000165266	SCV000911022	likely benign	Hereditary cancer-predisposing syndrome	2016-06-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000470788	SCV001520230	uncertain significance	Ataxia-telangiectasia syndrome	2019-09-06	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000165266	SCV002530998	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288745	SCV002580881	uncertain significance	Familial cancer of breast	2022-06-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000470788	SCV003827471	uncertain significance	Ataxia-telangiectasia syndrome	2022-07-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356838	SCV001552109	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ile550Val variant was identified in 1 of 384 proband chromosomes (frequency: 0.003) from individuals with breast cancer (Dork 2001). The variant was identified in dbSNP (rs202144949) as “with uncertain significance allele”, ClinVar (interpreted as "likely benign" by Color and 2 others and "uncertain significance by "Invitae"). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 10 of 277,036 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6458 chromosomes (freq: 0.0003), European in 5 of 126,552 chromosomes (freq: 0.00004), and South Asian in 3 of 30,778 chromosomes (freq: 0.0001). The variant was not observed in the African, Latino, Ashkenazi Jewish, or East Asian populations. The p.Ile550 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004552903	SCV004745456	uncertain significance	ATM-related disorder	2023-12-14	no assertion criteria provided	clinical testing	The ATM c.1648A>G variant is predicted to result in the amino acid substitution p.Ile550Val. This variant has previously been reported in two individuals with breast cancer (Dörk et al. 2001. PubMed ID: 11606401; Tavtigian. 2009. PubMed ID: 19781682). However, two closely related species harbor a valine at the p.Ile550 amino acid position. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185780/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.