Submissions for variant NM_000051.4(ATM):c.8805G>A (p.Met2935Ile)

gnomAD frequency: 0.00001  dbSNP: rs772621438

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467173	SCV000546958	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2935 of the ATM protein (p.Met2935Ile). This variant is present in population databases (rs772621438, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 28580595). ClinVar contains an entry for this variant (Variation ID: 407626). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The isoleucine 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	RCV000484203	SCV000570412	uncertain significance	not provided	2019-10-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer (Xie 2018); This variant is associated with the following publications: (PMID: 19781682, 28580595)
Ambry Genetics	RCV000561470	SCV000672700	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	clinical testing	The p.M2935I variant (also known as c.8805G>A), located in coding exon 60 of the ATM gene, results from a G to A substitution at nucleotide position 8805. The methionine at codon 2935 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in 1/292 individuals with breast cancer (Xie Y et al. Clin. Genet., 2018 Jan;93:41-51). This variant was also reported in 13/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561470	SCV001348006	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 2935 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been reported in a healthy control individual (PMID: 19781682). This variant has been identified in 9/251414 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484203	SCV002774800	uncertain significance	not provided	2021-08-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470428	SCV004209473	uncertain significance	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000467173	SCV002082781	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-17	no assertion criteria provided	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153615	SCV003843780	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing