Submissions for variant NM_000051.4(ATM):c.712A>G (p.Ile238Val)

gnomAD frequency: 0.00001  dbSNP: rs754275014

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165761	SCV000216506	likely benign	Hereditary cancer-predisposing syndrome	2019-04-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229485	SCV000283039	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-31	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 238 of the ATM protein (p.Ile238Val). This variant is present in population databases (rs754275014, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer, and ovarian cancer (PMID: 26689913, 27978560, 30287823). ClinVar contains an entry for this variant (Variation ID: 186210). 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. 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	RCV000235409	SCV000293178	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with melanoma, breast, ovarian, or colon cancer, and also in controls (PMID: 26689913, 27978560, 30287823, 34262154); This variant is associated with the following publications: (PMID: 26689913, 30287823, 27978560, 33471991, 34262154, 36243179)
Counsyl	RCV000229485	SCV000797968	uncertain significance	Ataxia-telangiectasia syndrome	2018-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165761	SCV000903358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 238 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, or colorectal cancer (PMID: 26689913, 27978560, 30287823, 33471991). This variant has been identified in 4/251040 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196993	SCV001367628	uncertain significance	Familial cancer of breast	2020-03-23	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235409	SCV001473895	uncertain significance	not provided	2020-02-01	criteria provided, single submitter	clinical testing	The ATM c.712A>G; p.Ile238Val variant (rs754275014) is reported in the literature in an individual with colorectal cancer (Pearlman 2017), and individuals with breast cancer but was also reported in healthy controls (Momozawa 2018). This variant is reported in the ClinVar database (Variation ID: 186210). It is found in the general population with an overall allele frequency of 0.002% (4/251040 alleles) in the Genome Aggregation Database. The isoleucine at codon 238 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471.
Sema4, Sema4	RCV000165761	SCV002536964	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
Baylor Genetics	RCV001196993	SCV004208185	uncertain significance	Familial cancer of breast	2024-02-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001196993	SCV005084825	likely benign	Familial cancer of breast	2024-04-22	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].