Submissions for variant NM_000051.4(ATM):c.2408T>C (p.Phe803Ser)

dbSNP: rs751218526

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484668	SCV000571099	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with endometrial carcinoma (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 26689913)
Color Diagnostics, LLC DBA Color Health	RCV000777664	SCV000913566	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 803 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 ATM-related disorders in the literature. This variant has been identified in 1/251270 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804031	SCV000943922	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 803 of the ATM protein (p.Phe803Ser). This variant is present in population databases (rs751218526, gnomAD 0.0009%). 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: 421790). 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 disruptive. 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	RCV000777664	SCV001176264	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-01	criteria provided, single submitter	clinical testing	The p.F803S variant (also known as c.2408T>C), located in coding exon 15 of the ATM gene, results from a T to C substitution at nucleotide position 2408. The phenylalanine at codon 803 is replaced by serine, an amino acid with highly dissimilar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000804031	SCV002077751	uncertain significance	Ataxia-telangiectasia syndrome	2021-01-13	no assertion criteria provided	clinical testing