Submissions for variant NM_000051.4(ATM):c.3175G>A (p.Ala1059Thr)

gnomAD frequency: 0.00004  dbSNP: rs370282831

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211995	SCV000149081	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer, Lynch syndrome-associated cancer and/or polyps, or CLL, and also seen in unaffected controls (Bernstein et al., 2010; Vollbrecht et al., 2015; Yurgelun et al., 2015; Decker et al., 2017; Tiao et al., 2017); This variant is associated with the following publications: (PMID: 25980754, 28779002, 28652578, 29778231, 19781682, 25356970, 32055024, 26053404, 20305132)
Ambry Genetics	RCV000115172	SCV000185778	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-12	criteria provided, single submitter	clinical testing	The p.A1059T variant (also known as c.3175G>A), located in coding exon 21 of the ATM gene, results from a G to A substitution at nucleotide position 3175. The alanine at codon 1059 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in 0/13087 breast cancer cases and 1/5488 control individuals in the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). 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	RCV000465718	SCV000546972	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515253	SCV000611356	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115172	SCV000687457	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1059 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 in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53460 controls (OR=0.442, 95%CI 0.015 to 13.178, p-value=0.469; PMID: 33471991). This variant has also been identified in 3/282670 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	RCV000779787	SCV000916585	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3175G>A (p.Ala1059Thr) results in a non-conservative amino acid change in 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 7.6e-06 in 262258 control chromosomes (gnomAD, Decker_2017). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3175G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome and Chronic Lymphocytic Leukemia (e.g. Bernstein_2010, Vollbrecht_2015, Yurgelun_2015) but it was also reported in controls (e.g. Decker_2017, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or 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: 20305132, 28779002, 29778231, 28652578, 26053404, 25980754, 33471991). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001249849	SCV001424011	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-05-14	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1059 in the ATM protein. This is a previously reported, rare variant in a control population dataset (gnomAD database, 3/277,044 alleles, 0.0011% overall frequency) that has been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). The Ala1059 residue is not located within a domain typically recognized as critical for ATM function in the DNA mismatch repair pathway. Bioinformatic tools queried are in disagreement with whether this alanine to threonine amino acid substitution would be damaging. The alanine residue at this position is only moderately evolutionarily conserved across mammalian species examined. All six ClinVar entries for this variant report the significance of this variant to be uncertain. Based upon the evidence, we also consider this to be a variant of uncertain significance.
Baylor Genetics	RCV003467024	SCV004208219	uncertain significance	Familial cancer of breast	2023-10-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467024	SCV004931080	likely benign	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].