ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1229T>C (p.Val410Ala) (rs56128736)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120171 SCV000149045 benign not specified 2016-11-29 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 RCV000119195 SCV000153936 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115136 SCV000172873 benign Hereditary cancer-predisposing syndrome 2014-07-13 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120171 SCV000232902 likely benign not specified 2015-04-01 criteria provided, single submitter clinical testing
Vantari Genetics RCV000115136 SCV000266989 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120171 SCV000593497 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115136 SCV000681959 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590142 SCV000694174 likely benign not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The ATM c.1229T>C (p.Val410Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 270/126714 control chromosomes (2 homozygotes) at a frequency of 0.0021308, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this variant is likely a benign polymorphism. This variant has been found in patients with various types of cancer, including breast cancer, uterine serous carcinoma, lymphoma, chronic lymphocytic leukemia, and melanoma. It has not been reported in patients with ataxia-telangiectasia. Two large case-control studies showed that this variant is not associated with breast cancer (Tavtigian 2009; Haiman 2013). Thus available patient and control data show that this variant is a polymorphism found in patients as well as unaffected individuals. In addition, three clinical laboratories have classified this variant as benign/likely benign albeit another lab consider it as uncertain significance, all without evidence to independently evaluate. Taken together, this variant has been classified as Likely benign until more evidence becomes available.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590142 SCV000780400 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Counsyl RCV000119195 SCV000788575 likely benign Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115136 SCV000803142 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590142 SCV000805492 likely benign not provided 2015-06-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000590142 SCV000840914 benign not provided 2017-09-11 criteria provided, single submitter clinical testing
Mendelics RCV000119195 SCV001138445 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283687 SCV001157044 benign none provided 2019-12-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119195 SCV001263700 likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000119195 SCV001439181 likely benign Ataxia-telangiectasia syndrome 2020-08-19 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000590142 SCV001714393 uncertain significance not provided 2019-04-21 criteria provided, single submitter clinical testing
ITMI RCV000120171 SCV000084313 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115136 SCV000787842 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356635 SCV001551859 likely benign Carcinoma of colon no assertion criteria provided clinical testing The ATM p.Val410Ala variant was identified in 5 of 1492 proband chromosomes (frequency: 0.003) from Dutch and Austrian individuals or families with breast cancer or ovarian cancer, and individuals with pediatric ALL (acute lymphocytic leukemia), and was identified in 2 of 644 chromosomes (frequency: 0.003) from healthy individuals (Broeks_2008_17393301, Thorstenson_2003_12810666, Liberzon_2004_14695997). The variant was also identified as a somatic mutation in 2 studies screening CRCs and lymphomas (Dallol_2016_ 27146902, Fang_2003_12149228). The variant was identified in dbSNP (ID: rs56128736) “With other allele”, ClinVar (wth conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics, GeneDx, and Invitae, likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), uncertain significance by Vantari Genetics and Genetic Services Laboratory (University of Chicago), and classification not provided by ITMI), Clinvitae (4x), Cosmic (7x in malignant melanoma, lymphoid neoplasm and carcinoma of the lung), LOVD 3.0, and in control databases in 582 (3 homozygous) of 276862 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 18 of 24018 chromosomes (freq: 0.0007), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 105 of 34390 chromosomes (freq: 0.003), European Non-Finnish in 401 (2 homozygous) of 126452 chromosomes (freq: 0.003), Ashkenazi Jewish in 41 (1 homozygous) of 10138 chromosomes (freq: 0.004), European Finnish in 3 of 25762 chromosomes (freq: 0.0001), while not observed in the East Asian and South Asian populations. The variant was not identified in GeneInsight-COGR or MutDB. The p.Val410 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ala to the protein; this information is not very predictive of 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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