Submissions for variant NM_000051.4(ATM):c.2804C>G (p.Thr935Arg)

dbSNP: rs3218708

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164443	SCV000215083	likely benign	Hereditary cancer-predisposing syndrome	2025-02-20	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	RCV000557491	SCV000622362	uncertain significance	Ataxia-telangiectasia syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 935 of the ATM protein (p.Thr935Arg). This variant is present in population databases (rs3218708, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, biliary tract cancer, uterus cancer (PMID: 25625042, 34326862, 36243179). ClinVar contains an entry for this variant (Variation ID: 185083). 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%. 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	RCV000164443	SCV000903257	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-29	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 935 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 (PMID: 25625042, 33471991). In a Japanese colorectal cancer risk case-control study, this variant was reported in 99/12502 colorectal cancer cases and 226/23704 controls (PMID: 33309985). This variant has been identified in 5/251396 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779788	SCV000916590	uncertain significance	not specified	2025-02-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2804C>G (p.Thr935Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 1660938 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00021 vs 0.004), allowing no conclusion about variant significance. c.2804C>G has been reported in the literature predominantly in reports of East Asian/Japanese cohorts of unaffected controls and in ethnicity-matched individuals affected with breast/colorectal cancer and/or with a personal/family history of cancer (example, Jiang_2018, Mangone_2015, Fujita_2020, Terashima_2019, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At least one recent report classifies this variant as benign based on a high frequency in Japanese population (Fujita_2020). It has also been reported at an allele frequency of 0.0061 in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN) dataset of 38,000 Japanese individuals, including 7 homozygotes, suggesting it is a benign polymorphism found primarily in individuals of East Asian/Japanese ancestry. 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: 33309985, 29642553, 25625042, 30287823, 31666926). ClinVar contains an entry for this variant (Variation ID: 185083). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030525	SCV001193473	likely benign	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000557491	SCV001263806	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV003238729	SCV003936415	uncertain significance	not provided	2023-02-22	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 or colorectal cancer as well as unaffected controls (Mangone et al., 2015; Momozawa et al., 2018; Fujita et al., 2020); This variant is associated with the following publications: (PMID: 25625042, 29642553, 33309985, 30287823, 31666926)
Counsyl	RCV000557491	SCV000800472	uncertain significance	Ataxia-telangiectasia syndrome	2018-06-07	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Natera, Inc.	RCV000557491	SCV001452053	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing