Submissions for variant NM_000051.4(ATM):c.5080G>A (p.Ala1694Thr)

gnomAD frequency: 0.00001  dbSNP: rs756197350

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462765	SCV000546963	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1694 of the ATM protein (p.Ala1694Thr). This variant is present in population databases (rs756197350, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 25503501, 28135145). ClinVar contains an entry for this variant (Variation ID: 407631). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000481315	SCV000565854	uncertain significance	not provided	2024-02-28	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; This variant is associated with the following publications: (PMID: 25503501, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000583320	SCV000687606	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1694 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 breast cancer (PMID: 25503501), an individual affected with colorectal cancer (PMID: 28135145), and in a healthy individual (PMID: 33471991). This variant has been identified in 2/251230 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.
Counsyl	RCV000462765	SCV000790892	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000583320	SCV001185402	likely benign	Hereditary cancer-predisposing syndrome	2018-02-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492053	SCV004239294	uncertain significance	Breast and/or ovarian cancer	2022-12-19	criteria provided, single submitter	clinical testing