Submissions for variant NM_000051.4(ATM):c.5300T>G (p.Phe1767Cys)

dbSNP: rs864622125

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206146	SCV000259397	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 219503). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1767 of the ATM protein (p.Phe1767Cys).
Color Diagnostics, LLC DBA Color Health	RCV000777915	SCV000913954	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-12	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 1767 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics	RCV000777915	SCV001185829	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	clinical testing	The p.F1767C variant (also known as c.5300T>G), located in coding exon 34 of the ATM gene, results from a T to G substitution at nucleotide position 5300. The phenylalanine at codon 1767 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001549797	SCV001770013	uncertain significance	not provided	2019-12-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003462363	SCV004217151	uncertain significance	Familial cancer of breast	2023-05-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000206146	SCV001551282	uncertain significance	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing	The ATM p.Phe1767Cys variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs864622125) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae). The variant was not identified in the following databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Phe1767 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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
Natera, Inc.	RCV000206146	SCV002081826	uncertain significance	Ataxia-telangiectasia syndrome	2020-10-22	no assertion criteria provided	clinical testing