ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6995T>C (p.Leu2332Pro) (rs4988111)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120156 SCV000167054 benign not specified 2013-10-01 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 RCV000128891 SCV000172751 benign Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Invitae RCV001080466 SCV000262433 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224405 SCV000281631 likely benign not provided 2016-02-11 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Color Health, Inc RCV000128891 SCV000682382 benign Hereditary cancer-predisposing syndrome 2014-11-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120156 SCV000703941 benign not specified 2016-12-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120156 SCV000805611 benign not specified 2016-10-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001080466 SCV001260754 benign Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
ITMI RCV000120156 SCV000084297 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000128891 SCV000805220 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing
Natera, Inc. RCV001080466 SCV001452131 benign Ataxia-telangiectasia syndrome 2020-01-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357692 SCV001553236 benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Leu2332Pro variant was identified in 6 of 2720 proband chromosomes (frequency: 0.002) from American and Brazilian individuals or families with Lynch syndrome or sporadic breast cancer and was not identified in 200 chromosomes from healthy individuals (Yurgelun_2015_25980754 , Mangone_2015_25625042). The variant was also identified in dbSNP (ID: rs4988111) “With Likely benign, Uncertain significance allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae; likely benign by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics); and classification not provided by ITMI), Clinvitae (4x); and was not identified in GeneInsight-COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 557 (7 homozygous) of 276772 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 515 (7 homozygous) of 24026 chromosomes (freq: 0.02), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 27 of 34410 chromosomes (freq: 0.0008), European Non-Finnish in 9 of 126350 chromosomes (freq: 0.00007), Ashkenazi Jewish in 1 of 10138 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003) while not observed in the East Asian and European Finnish, populations. The p.Leu2332 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Pro impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000120156 SCV001739751 benign not specified no assertion criteria provided clinical testing

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