Submissions for variant NM_000051.4(ATM):c.1272T>C (p.Pro424=)

gnomAD frequency: 0.00019  dbSNP: rs35578748

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122817	SCV000166074	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000211959	SCV000209587	benign	not specified	2014-09-28	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.
Ambry Genetics	RCV000159603	SCV000213198	likely benign	Hereditary cancer-predisposing syndrome	2014-07-08	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.
Illumina Laboratory Services, Illumina	RCV000122817	SCV000367028	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	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.
Color Diagnostics, LLC DBA Color Health	RCV000159603	SCV000537415	likely benign	Hereditary cancer-predisposing syndrome	2015-07-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211959	SCV000694176	likely benign	not specified	2018-11-12	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1272T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 274872 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00028 vs 0.004), allowing no conclusion about variant significance. c.1272T>C has been reported in the literature in an individual affected with Breast Cancer (Bernstein 2010), however this report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrence with another pathogenic variant have been reported (ATM c.6095G>A, in an internal sample), providing supporting evidence for a benign role. In addition, the variant was reported in 4 / 7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 classifying the variant as benign, 2 calling it likely benign, and one as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000588662	SCV000805494	likely benign	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000122817	SCV001138463	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588662	SCV001148403	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	ATM: BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211959	SCV001469345	benign	not specified	2020-03-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000211959	SCV001476944	benign	not specified	2020-03-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798388	SCV002042284	likely benign	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211959	SCV002070868	likely benign	not specified	2021-07-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159603	SCV002530242	likely benign	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211959	SCV002760522	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589593	SCV005083836	benign	Familial cancer of breast	2024-04-26	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Natera, Inc.	RCV000122817	SCV001461080	likely benign	Ataxia-telangiectasia syndrome	2020-01-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355372	SCV001550244	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Pro424Pro variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs35578748) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: benign by Invitae, GeneDx; likely benign by Ambry Genetics, Color Genomics; and uncertain significance by Illumina), Clinvitae (3x), and in control databases in 76 of 274872 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 23952 chromosomes (frequency: 0.00004), Other in 3 of 6438 chromosomes (frequency: 0.0004), Latino in 5 of 34362 chromosomes (frequency: 0.0001), European Non-Finnish in 54 of 126046 chromosomes (frequency: 0.0004), Ashkenazi Jewish in 4 of 10126 chromosomes (frequency: 0.0004), and South Asian in 9 of 30698 chromosomes (frequency: 0.0003). The variant was identified in our laboratory in 1 individual, co-occurring with a large pathogenic genomic deletion (EPCAM c.185-?_MSH2:c.366+?del) increasing the likelihood that the p.Pro424= variant does not have clinical significance. In addition, the p.Pro424= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588662	SCV001808319	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588662	SCV001906062	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588662	SCV001956697	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588662	SCV001968216	likely benign	not provided		no assertion criteria provided	clinical testing