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

gnomAD frequency: 0.00022  dbSNP: rs2235011

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122833	SCV000166091	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129351	SCV000184115	likely benign	Hereditary cancer-predisposing syndrome	2024-01-23	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.
GeneDx	RCV000586568	SCV000209699	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Observed in individuals with breast, thyroid, colorectal, prostate, and/or endometrial cancer (PMID: 20305132, 29684080, 31206626, 34250417, 35666082); In silico analysis indicates 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, 34250417, 35666082)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002223130	SCV000694215	uncertain significance	not specified	2024-06-28	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 Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2281A>T has been reported in the literature in individuals affected with breast cancer and in individuals 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, Purrington_2020). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or other ATM-related disorders. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 22529920, 17132159, 35666082, 34250417, 19781682, 11443540, 31206626, 32868316). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 135744). 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
Myriad Genetics, Inc.	RCV004589597	SCV005083880	likely benign	Familial cancer of breast	2024-05-08	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.	RCV000122833	SCV001462061	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551196	SCV004723810	uncertain significance	ATM-related disorder	2024-02-15	no assertion criteria provided	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.