Submissions for variant NM_000051.4(ATM):c.2698A>G (p.Met900Val)

gnomAD frequency: 0.00001  dbSNP: rs138468963

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165046	SCV000215746	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-31	criteria provided, single submitter	clinical testing	The p.M900V variant (also known as c.2698A>G), located in coding exon 17 of the ATM gene, results from an A to G substitution at nucleotide position 2698. The methionine at codon 900 is replaced by valine, an amino acid with highly similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231617	SCV000282908	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-28	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 900 of the ATM protein (p.Met900Val). This variant is present in population databases (rs138468963, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 185598). 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	RCV000165046	SCV000903928	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 900 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 an individual undergoing tested for hereditary breast and ovarian cancer (PMID: 38136308). This variant has been identified in 5/282788 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.
Baylor Genetics	RCV003468729	SCV004210189	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV004719725	SCV005325665	uncertain significance	not provided	2023-11-26	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; Observed in individuals with a personal and/or family history suggestive of hereditary breast and ovarian cancer (PMID: 31742824); This variant is associated with the following publications: (PMID: 31742824)
Natera, Inc.	RCV000231617	SCV002078849	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-30	no assertion criteria provided	clinical testing