Submissions for variant NM_000051.4(ATM):c.2635A>G (p.Ile879Val)

gnomAD frequency: 0.00001  dbSNP: rs556598169

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159759	SCV000209778	uncertain significance	not provided	2023-12-20	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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; A large meta-analysis found this variant to be absent in breast cancer patients (0/2,531) but present in three control subjects (3/2,245) (PMID: 19781682); Observed in individuals with non-Hodgkin lymphoma, pancreatic cancer, or clinically high-risk breast and/or ovarian cancer (PMID: 17640065, 32068069, 35171259); This variant is associated with the following publications: (PMID: 35171259, 32068069, 19781682, 17640065)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469928	SCV000546738	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-13	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 879 of the ATM protein (p.Ile879Val). This variant is present in population databases (rs556598169, gnomAD 0.006%). This missense change has been observed in individual(s) with ATM-related conditions (PMID: 17640065, 32068069, 35171259). ClinVar contains an entry for this variant (Variation ID: 181990). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Ambry Genetics	RCV000568728	SCV000660699	likely benign	Hereditary cancer-predisposing syndrome	2025-02-25	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235076	SCV003934538	uncertain significance	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2635A>G (p.Ile879Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251378 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2635A>G has been reported in the literature in individuals affected with non-Hodgkin lymphoma, breast cancer, and pancreatic cancer without strong evidence of causality (Sipahimalani_2007, Kwong_2020, Yin_2022). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17640065, 32068069, 35171259). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000568728	SCV004360701	uncertain significance	Hereditary cancer-predisposing syndrome	2025-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 879 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. In a large international case-control study, this variant was reported in 7/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant was also reported in an individual affected with pancreatic ductal adenocarcinoma (PMID: 35171259). This variant has been identified in 3/251378 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.
Fulgent Genetics, Fulgent Genetics	RCV005042315	SCV005681244	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-06-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359343	SCV005913669	uncertain significance	Familial cancer of breast	2024-03-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000469928	SCV001462080	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing