ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4402G>A (p.Val1468Ile) (rs369903995)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115194 SCV000186529 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115194 SCV000911162 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656760 SCV000228684 uncertain significance not provided 2015-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000656760 SCV000149103 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.4402G>A at the cDNA level, p.Val1468Ile (V1468I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has been observed in an individual with MMR-proficient colorectal cancer (Pearlman 2017). ATM Val1468Ile was also identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. ATM Val1468Ile was observed at an allele frequency of 0.08% (18/23,982) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val1468Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120138 SCV000084278 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120138 SCV000918526 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.4402G>A (p.Val1468Ile) results in a conservative amino acid change located in the Armadillo-type fold of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.0001 in 276692 control chromosomes (gnomAD). The variant was predominantly observed in the African cohort at an allele frequency of 0.00075 (18/23982), which is comparable to the estimated expected allele frequency for a pathogenic variant in ATM causing Breast Cancer (0.00075 vs. 0.001). Another database, FLOSSIES, that contains unaffected individuals older than 70 years of age, observed the variant in 6/2559 African Americans, combining this data with the gnomAD occurrences, 24/26541 chromosomes (allele frequency of 0.0009), therefore, could suggest the variant is a benign polymorphism found in populations of African origin. The variant, c.4402G>A, has been reported in the literature in an individual diagnosed with Colon cancer (Pearlman 2016). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as "VUS - possibly benign."
Invitae RCV000199082 SCV000254107 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1468 of the ATM protein (p.Val1468Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs369903995, ExAC 0.09%). This variant has been reported in an individual affected with colorectal cancer (PMID: 2798560). ClinVar contains an entry for this variant (Variation ID: 127389). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000199082 SCV000838540 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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