Submissions for variant NM_000051.4(ATM):c.1049C>T (p.Ala350Val)

gnomAD frequency: 0.00001  dbSNP: rs375049090

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230455	SCV000282859	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 350 of the ATM protein (p.Ala350Val). This variant is present in population databases (rs375049090, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 27553368, 35264596). ClinVar contains an entry for this variant (Variation ID: 236665). 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	RCV000564026	SCV000665530	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	The p.A350V variant (also known as c.1049C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1049. The alanine at codon 350 is replaced by valine, an amino acid with similar properties. This alteration was identified in 1/80 Portuguese patients with hereditary breast cancer who had negative BRCA1/2 testing (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159(2):245-56). 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.
Mendelics	RCV000230455	SCV000838480	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564026	SCV000904436	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 350 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. This variant has been reported with a PALB2 truncation (c.1633G>T, p.Glu545*) in an individual affected with breast cancer (PMID: 27553368). This variant has been identified in 2/251126 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.
Fulgent Genetics, Fulgent Genetics	RCV002487044	SCV002784055	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000230455	SCV002090279	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-19	no assertion criteria provided	clinical testing