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

gnomAD frequency: 0.00001  dbSNP: rs375049090

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230455	SCV000282859	uncertain significance	Ataxia-telangiectasia syndrome	2024-08-01	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, 35534704). 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	2024-01-18	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 has been identified in individuals diagnosed with breast cancer (Pinto P et al. Breast Cancer Res Treat, 2016 Sep;159:245-56; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, 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
Baylor Genetics	RCV004567701	SCV005057103	uncertain significance	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998501	SCV005624741	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005406972	SCV006072113	uncertain significance	not specified	2025-03-19	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1049C>T (p.Ala350Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1049C>T has been reported in the literature in individuals affected with a personal or family history of Breast and/or Ovarian Cancer (Pinto_2016, Giboni_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35957908, 27553368). ClinVar contains an entry for this variant (Variation ID: 236665). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000230455	SCV002090279	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-19	no assertion criteria provided	clinical testing