Submissions for variant NM_000051.4(ATM):c.6899G>C (p.Trp2300Ser)

dbSNP: rs1555119899

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000677225	SCV002198877	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-28	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. 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 expected to disrupt ATM protein function. ClinVar contains an entry for this variant (Variation ID: 559541). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 30888062). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with serine at codon 2300 of the ATM protein (p.Trp2300Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine.
3billion	RCV000677225	SCV002521509	likely pathogenic	Ataxia-telangiectasia syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ATM related disorder (ClinVar ID: VCV000559541 / PMID: 30888062). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 30888062). A different missense change at the same codon (p.Trp2300Gly) has been reported to be associated with ATM related disorder (PMID: 33098801). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
HUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP)	RCV000677225	SCV000788257	likely pathogenic	Ataxia-telangiectasia syndrome	2018-07-26	no assertion criteria provided	clinical testing	This variant (NM_000051.3:c.6899G>C) is seen in compound heterozygosity with the variant NG_009830.1(NM_000051.3):c.(2466+1_2467-1)_(8850+1_8851-1)dup in the affected child.