ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2630G>C (p.Ser877Thr) (rs370269552)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211985 SCV000149070 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.2630G>C at the cDNA level, p.Ser877Thr (S877T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). In a large meta-analysis by Tavtigian et al. (2009), this variant was reported at similar frequencies in breast cancer cases (3/2531) and controls (3/2245). ATM Ser877Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Ser877Thr 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 Ser877Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115161 SCV000184961 likely benign Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);in silico models in agreement (benign)
Invitae RCV001083203 SCV000219104 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000115161 SCV000910866 benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174578 SCV001337756 uncertain significance not specified 2020-01-10 criteria provided, single submitter clinical testing Variant summary: ATM c.2630G>C (p.Ser877Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251400 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2630G>C has been reported in the literature in individuals affected with Breast Cancer and lung cancer as well as in controls (Bernstein_2010, Chan_2018, Lu_2015, Parry_2017, Tavtigian_2009). These reports do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x benign/likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.

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