Submissions for variant NM_000051.4(ATM):c.2887A>G (p.Met963Val)

gnomAD frequency: 0.00015  dbSNP: rs374353016

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132462	SCV000187556	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	The p.M963V variant (also known as c.2887A>G), located in coding exon 18 of the ATM gene, results from an A to G substitution at nucleotide position 2887. The methionine at codon 963 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in breast cancer cohorts (Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This variant has also been identified in 1/12503 unselected Japanese colorectal cancer patients and in 0/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 09;20:2132-2141.e9). This alteration has been observed in a cohort of 1040 patients with advanced cancer who were tested for germline mutations in 76 cancer predisposition genes (Mandelker D et al. JAMA. 2017 09;318:825-835). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168295	SCV000218973	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000236226	SCV000292902	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 32866190, 36568162, 32885271, 33309985, 28873162, 29684080, 33471991, 33939675)
Color Diagnostics, LLC DBA Color Health	RCV000132462	SCV000903008	likely benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000236226	SCV001143103	uncertain significance	not provided	2022-11-04	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201309	SCV001372448	uncertain significance	not specified	2023-05-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2887A>G (p.Met963Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 298826 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.2887A>G has been reported in the literature in individuals affected with different types of cancer, including Breast, Pancreatic and Colorectal Cancers (examples: Mandelker_2017, Yehia_2018, Bishop_2020, Fujita_2020, van der Merwe_2022, Zhu_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.658_659delGT, p.Val220IlefsX4, Yehia_2018), providing supporting evidence for a benign role. 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: 28873162, 29684080, 33309985, 32866190, 33939675, 36568162). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798460	SCV002042010	uncertain significance	Breast and/or ovarian cancer	2022-04-29	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225449	SCV002505338	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132462	SCV002532930	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Natera, Inc.	RCV000168295	SCV001462129	uncertain significance	Ataxia-telangiectasia syndrome	2020-04-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355859	SCV001550865	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Met963Val variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, or LOVD 3.0 database. The variant was identified in dbSNP (ID: rs374353016) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and GeneDx). The variant was identified in control databases in 13 of 277192 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24032 chromosomes (freq: 0.0004), Latino in 2 of 34416 chromosomes (freq: 0.00006), European in 1 of 126700 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met963 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.