Submissions for variant NM_000051.4(ATM):c.175G>T (p.Ala59Ser)

gnomAD frequency: 0.00002  dbSNP: rs752527112

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214079	SCV000277966	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-16	criteria provided, single submitter	clinical testing	The p.A59S variant (also known as c.175G>T), located in coding exon 2 of the ATM gene, results from a G to T substitution at nucleotide position 175. The alanine at codon 59 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557155	SCV000622279	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 59 of the ATM protein (p.Ala59Ser). This variant is present in population databases (rs752527112, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 233566). 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 not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000214079	SCV000913528	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 59 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). Experimental studies have shown that this variant causes a partial loss of function (PMID: 29059438). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 25186627). This variant has been identified in 3/250704 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194331	SCV001363788	uncertain significance	not specified	2019-11-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.175G>T (p.Ala59Ser) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair (TAN) motif (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250704 control chromosomes (gnomAD), exclusively reported within the African or African-American subpopulation (3 /16120 alleles). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.175G>T has been reported in the literature in an individual of African ancestry who was affected with Breast Cancer (Tung_2015). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein moderately reversed the hyperradiosensitivity phenotype of ATM-null cells, but resulted in increased radiosensitivity compared to ATM wild-type cells, indicating a partial loss of function (Takagi_2017). These data do not allow clear conclusions about the variant significance. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003469081	SCV004210064	uncertain significance	Familial cancer of breast	2023-08-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000557155	SCV001461810	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing