Submissions for variant NM_000051.4(ATM):c.8671+9T>G

gnomAD frequency: 0.00013  dbSNP: rs200190537

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000123717	SCV000167060	benign	not specified	2014-02-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000988738	SCV000252989	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000448274	SCV000537424	likely benign	Hereditary cancer-predisposing syndrome	2015-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123717	SCV000694383	likely benign	not specified	2023-04-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8671+9T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict no significant impact on normal splicing while two predict the variant strengthens an alternate cryptic intronic 5' donor site located position c.8671+4 in the gene sequence. However, any in-vivo consequences of these predictions have yet to be confirmed and/or reported by functional studies. The variant allele was found at a frequency of 0.00012 in 249426 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00012 vs 0.004), allowing no conclusion about variant significance. c.8671+9T>G has been reported in the literature in at-least one individual with 11q CLL (Skowronska_2012). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or breast/CLL cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as ikely benign (n=6) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000589757	SCV000805630	likely benign	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000988738	SCV001138584	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988738	SCV001264809	uncertain significance	Ataxia-telangiectasia syndrome	2018-03-30	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
MGZ Medical Genetics Center	RCV002288615	SCV002581601	uncertain significance	Familial cancer of breast	2022-07-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123717	SCV004024612	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000988738	SCV002082670	likely benign	Ataxia-telangiectasia syndrome	2020-01-30	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123717	SCV003840103	likely benign	not specified	2022-04-13	no assertion criteria provided	clinical testing