Submissions for variant NM_000051.4(ATM):c.7999A>G (p.Met2667Val)

gnomAD frequency: 0.00003  dbSNP: rs34099398

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130136	SCV000184969	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The p.M2667V variant (also known as c.7999A>G), located in coding exon 53 of the ATM gene, results from an A to G substitution at nucleotide position 7999. The methionine at codon 2667 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in multiple breast cancer cohorts as well and unaffected control groups across studies (Renwick A et al. Nat Genet, 2006 Aug;38:873-5; Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46; Young EL et al. J Med Genet, 2016 06;53:366-76; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been reported in an individual affected with colorectal cancer, who was also identified to carry a pathogenic mutation in ATM (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000416016	SCV000493557	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474473	SCV000546996	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-18	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 2667 of the ATM protein (p.Met2667Val). This variant is present in population databases (rs34099398, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer or breast cancer (PMID: 19781682, 28135145). ClinVar contains an entry for this variant (Variation ID: 141559). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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	RCV000416016	SCV000564664	uncertain significance	not provided	2023-09-06	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 with a reportedly pathogenic ATM variant, phase (cis or trans) unknown, in a patient with colorectal cancer (Yurgelun et al., 2017); Observed in individuals with breast cancer, but also in healthy controls (Renwick et al., 2006; Tavtigian et al., 2009; Bhai et al., 2021); This variant is associated with the following publications: (PMID: 26787654, 26727500, 22529920, 33471991, 16832357, 34326862, 19781682, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000130136	SCV000903238	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 2667 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in unaffected individuals (PMID: 16832357, 19781682, 33471991; Color Health internal data). This variant also has been reported in an individual affected with colorectal cancer, although the individual was found to also have a co-occuring ATM germline mutation (PMID: 28135145). This variant has been identified in 4/282418 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798440	SCV002042968	uncertain significance	Breast and/or ovarian cancer	2020-04-02	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288635	SCV002580859	uncertain significance	Familial cancer of breast	2022-06-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288635	SCV004210218	uncertain significance	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288635	SCV005084990	likely benign	Familial cancer of breast	2024-06-18	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].
Natera, Inc.	RCV000474473	SCV002076807	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739439	SCV005348924	uncertain significance	ATM-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The ATM c.7999A>G variant is predicted to result in the amino acid substitution p.Met2667Val. This variant has been reported as a variant of uncertain significance in an individual with a personal and family history of colorectal cancer (Yurgelun et al. 2017. PubMed ID: 28135145). Of note, this individual also had another pathogenic germline variant in ATM (Yurgelun et al. 2017. PubMed ID: 28135145). In an analysis of individuals with breast cancer, this variant was found equally among individuals with cancer and controls (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141559/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.