ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.946T>C (p.Tyr316His) (rs142317485)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000234905 SCV000273499 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000234905 SCV000292194 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000486900 SCV000567682 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.946T>C at the cDNA level, p.Tyr316His (Y316H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant was observed in peripheral blood samples from at least two individuals with chronic lymphocytic leukemia, one individual with breast cancer, and unaffected controls (Athanasakis 2014, Rigolin 2016, Decker 2017, Tiao 2017). ATM Tyr316His was not observed at a significant allele frequency 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr316His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204232 SCV000260995 uncertain significance Ataxia-telangiectasia syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 316 of the ATM protein (p.Tyr316His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs142317485, ExAC 0.01%). This variant has been reported in one individual affected with breast cancer and two individuals in the control group (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 220453). 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 disruptive, 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.

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