Submissions for variant NM_000051.4(ATM):c.2606C>T (p.Ala869Val)

dbSNP: rs145513717

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166230	SCV000217009	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.A869V variant (also known as c.2606C>T), located in coding exon 16 of the ATM gene, results from a C to T substitution at nucleotide position 2606. The alanine at codon 869 is replaced by valine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not 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	RCV000225924	SCV000282906	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-01	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 869 of the ATM protein (p.Ala869Val). This variant is present in population databases (rs145513717, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 186608). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV000487118	SCV000564619	uncertain significance	not provided	2024-03-29	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; Observed in individuals with breast cancer, but also in unaffected controls (PMID: 28779002, 29684080, 33471991); This variant is associated with the following publications: (PMID: 28779002, 29684080, 33471991)
Counsyl	RCV000225924	SCV000789211	uncertain significance	Ataxia-telangiectasia syndrome	2017-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166230	SCV000911327	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 869 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. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251432 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.
Baylor Genetics	RCV000225924	SCV001520231	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844060	SCV002103529	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2606C>T (p.Ala869Val) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251432 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2606C>T has been reported in the literature in individuals affected with breast cancer (e.g. Dorling_2021), without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33471991). ClinVar contains an entry for this variant (Variation ID: 186608). Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153451	SCV003843061	uncertain significance	Familial cancer of breast	2023-02-23	criteria provided, single submitter	clinical testing	The ATM c.2606C>T (p.Ala869Val) missense change has a maximum subpopulation frequency of 0.0026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. A case-control study of 13,087 breast cancer patients and 5,488 controls indicated that the variant is present in approximately equal proportions of cases and controls with an odds ratio of <1 (PMID: 28779002). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003153451	SCV004207684	uncertain significance	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000225924	SCV004234536	uncertain significance	Ataxia-telangiectasia syndrome	2023-03-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042336	SCV005681242	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-06-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000225924	SCV002076331	uncertain significance	Ataxia-telangiectasia syndrome	2020-11-24	no assertion criteria provided	clinical testing