Submissions for variant NM_000051.4(ATM):c.7816A>G (p.Ile2606Val)

gnomAD frequency: 0.00004  dbSNP: rs376824528

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166765	SCV000217578	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7816. The isoleucine at codon 2606 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000197716	SCV000254152	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2606 of the ATM protein (p.Ile2606Val). This variant is present in population databases (rs376824528, gnomAD 0.004%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 187077). 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 tolerated. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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	RCV000513206	SCV000564661	uncertain significance	not provided	2023-04-24	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; Published functional studies suggest a minimal effect on splicing compared to controls (Dragos et al., 2022); Observed in individuals with a personal and/or family history of breast, ovarian, prostate, and other cancers (Tung et al., 2015; Karlsson et al., 2021; Andrikopoulou et al., 2022; Dragos et al., 2022); This variant is associated with the following publications: (PMID: 23338612, 25428177, 33436325, 35806449, 36531003, 25186627)
CeGaT Center for Human Genetics Tuebingen	RCV000513206	SCV000608619	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625763	SCV000746305	uncertain significance	not specified	2020-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000513206	SCV000805619	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000197716	SCV000838598	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166765	SCV000902970	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2606 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). RNA studies have showed this variant causes a minor increase in exon 53 skipping (PMID: 35806449). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 35806449), ovarian cancer (PMID: 36531003), or prostate cancer (PMID: 33436325). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054, p-value=1; PMID: 33471991). This variant has also been identified in 4/250604 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV002265647	SCV002548546	uncertain significance	Familial cancer of breast	2022-05-15	criteria provided, single submitter	clinical testing	ATM:c.7816A>G variant is predicted to create a de novo donor ss 28 bp upstream of natural splice site. Functional RNA study has shown that the variant may cause minimally expressed whole exon 53 skipping (PMID: 35806449). Missense in silico tools predict that the variant does not have an impact on protein function (REVEL 0.26). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PP3)
Fulgent Genetics, Fulgent Genetics	RCV002485035	SCV002787210	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002265647	SCV004019654	likely benign	Familial cancer of breast	2023-03-31	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].
Baylor Genetics	RCV002265647	SCV004207706	uncertain significance	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000197716	SCV001462595	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing