Submissions for variant NM_000051.4(ATM):c.3843T>G (p.Ser1281Arg)

dbSNP: rs863224565

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199552	SCV000254093	uncertain significance	Ataxia-telangiectasia syndrome	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1281 of the ATM protein (p.Ser1281Arg). This variant is not present in population databases (gnomAD no frequency). 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: 216206). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000567335	SCV000665499	likely benign	Hereditary cancer-predisposing syndrome	2024-07-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000567335	SCV001357032	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1281 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. In a large breast cancer case-control study, this variant was reported in 1/60465 cases and 1/53460 controls (OR=0.884, 95%CI 0.055 to 14.136, p-value=1; PMID: 33471991). This variant has not been identified 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.
GeneDx	RCV001555609	SCV001777055	uncertain significance	not provided	2019-05-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28259476)
Baylor Genetics	RCV003462317	SCV004215512	uncertain significance	Familial cancer of breast	2023-05-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000199552	SCV002081448	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-21	no assertion criteria provided	clinical testing