Submissions for variant NM_000051.4(ATM):c.2281A>T (p.Thr761Ser)

gnomAD frequency: 0.00022  dbSNP: rs2235011

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122833	SCV000166091	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129351	SCV000184115	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.T761S variant (also known as c.2281A>T), located in coding exon 14 of the ATM gene, results from an A to T substitution at nucleotide position 2281. The threonine at codon 761 is replaced by serine, an amino acid with similar properties. This alteration has been detected in 0/4,112 breast cancer patients and 1/2,399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This alteration was detected in 1/1,054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1,189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
GeneDx	RCV000586568	SCV000209699	uncertain significance	not provided	2023-06-26	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: 22529920, 19781682, 11443540, 20305132, 29684080, 31206626, 17132159)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002223130	SCV000694215	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2281A>T (p.Thr761Ser) 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 4.4e-05 in 251418 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.4e-05 vs 0.004), allowing no conclusion about variant significance. c.2281A>T has been reported in the literature in individuals affected with breast cancer, undertaking colorectal or prostate cancer panel testing, as well as in healthy controls (example, Giri_2022, Pearlman_2021, Einarsdottir_2005, Tavtigian_2009, Bernstein_2010, Weitzel_2019), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM related cancers. 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: 20305132, 22529920, 17132159, 35666082, 34250417, 19781682, 11443540, 31206626). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=5; Likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129351	SCV000911210	likely benign	Hereditary cancer-predisposing syndrome	2020-08-27	criteria provided, single submitter	clinical testing
Mendelics	RCV002223130	SCV002516942	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129351	SCV002529831	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003905174	SCV004723810	uncertain significance	ATM-related condition	2024-02-15	criteria provided, single submitter	clinical testing	The ATM c.2281A>T variant is predicted to result in the amino acid substitution p.Thr761Ser. This variant has been reported in patients with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626) as well as in controls without cancer (Thorstenson et al. 2001. PubMed ID 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has also been reported in a study of patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and is has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000122833	SCV001462061	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing