Submissions for variant NM_000051.4(ATM):c.3190A>G (p.Met1064Val)

gnomAD frequency: 0.00001  dbSNP: rs79431304

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214272	SCV000273017	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.M1064V variant (also known as c.3190A>G), located in coding exon 21 of the ATM gene, results from an A to G substitution at nucleotide position 3190. The methionine at codon 1064 is replaced by valine, an amino acid with highly similar properties. 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.
Counsyl	RCV000671975	SCV000797024	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671975	SCV000820927	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1064 of the ATM protein (p.Met1064Val). This variant is present in population databases (rs79431304, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 28135048). ClinVar contains an entry for this variant (Variation ID: 229707). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter 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.
Color Diagnostics, LLC DBA Color Health	RCV000214272	SCV000911185	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1064 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 been identified in 3/251322 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.
GeneDx	RCV001546529	SCV001766061	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and also in unaffected controls (Liu et al., 2017; Momozawa et al., 2018; Xie et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 30287823, 28135048, 28580595, 19781682, 33471991)
Sema4, Sema4	RCV000214272	SCV002533620	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-10	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153495	SCV003843550	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468979	SCV004212149	uncertain significance	Familial cancer of breast	2022-12-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000671975	SCV001452066	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing