Submissions for variant NM_000051.4(ATM):c.9002G>A (p.Ser3001Asn)

dbSNP: rs587781413

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217769	SCV000275892	likely benign	Hereditary cancer-predisposing syndrome	2023-12-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555618	SCV000622875	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 3001 of the ATM protein (p.Ser3001Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, and/or ovarian cancer (PMID: 26837699, 30723761, 34646395). ClinVar contains an entry for this variant (Variation ID: 231903). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000217769	SCV000687869	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 3001 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 an individual affected with breast cancer (PMID: 34646395) and in two individuals affected by chronic lymphocytic leukemia (PMID: 26837699). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000994721	SCV001148455	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193665	SCV001362659	uncertain significance	not specified	2019-10-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.9002G>A (p.Ser3001Asn) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9002G>A has been reported in the literature in an individual with ovarian endometrioid adenocarcinoma with yolk sac differentiation and Lynch syndrome (Sookram_2019). This patient also carried another pathogenic MSH2 variant, c.2038C>T (p.R680X). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001193665	SCV002071367	uncertain significance	not specified	2019-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217769	SCV002530603	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002478796	SCV002793699	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000994721	SCV004022795	uncertain significance	not provided	2023-07-18	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; This variant is associated with the following publications: (PMID: 23532176, 34646395, 30723761, 26837699)
Baylor Genetics	RCV004567583	SCV005057092	uncertain significance	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000555618	SCV001452587	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing