Submissions for variant NM_000051.4(ATM):c.5096C>T (p.Ala1699Val)

dbSNP: rs992234584

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779794	SCV000916598	uncertain significance	not specified	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5096C>T (p.Ala1699Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245964 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5096C>T has been reported in the literature in FFPE tissue specimens from colorectal tumors, thus these reports do not provide unequivocal conclusions about the germline association of the variant with Ataxia-Telangiectasia or cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001023528	SCV001185426	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-25	criteria provided, single submitter	clinical testing	The p.A1699V variant (also known as c.5096C>T), located in coding exon 33 of the ATM gene, results from a C to T substitution at nucleotide position 5096. The alanine at codon 1699 is replaced by valine, 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.
Color Diagnostics, LLC DBA Color Health	RCV001023528	SCV001355259	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1699 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 not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308098	SCV001497534	uncertain significance	Ataxia-telangiectasia syndrome	2023-08-16	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 1699 of the ATM protein (p.Ala1699Val). This variant is not present in population databases (gnomAD no frequency). 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: 632654). 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.
Baylor Genetics	RCV004569486	SCV005053039	uncertain significance	Familial cancer of breast	2023-11-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001308098	SCV002078462	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-03	no assertion criteria provided	clinical testing