ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3630G>A (p.Met1210Ile) (rs587778073)

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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 RCV000131218 SCV000186170 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000476722 SCV000546916 uncertain significance Ataxia-telangiectasia syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1210 of the ATM protein (p.Met1210Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs587778073, ExAC 0.003%). This variant has been reported in individuals affected with breast cancer (PMID: 11996792, 19781682). ClinVar contains an entry for this variant (Variation ID: 133616). 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.
GeneDx RCV000657063 SCV000567976 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.3630G>A at the cDNA level, p.Met1210Ile (M1210I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has been observed in several individuals with breast cancer (Sommer 2002, Tavtigian 2009, Decker 2017, Hauke 2018). ATM Met1210Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the bata-adaptin interaction domain (Tavtigian 2009). 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 Met1210Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000120134 SCV000593501 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Color RCV000131218 SCV000682153 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000476722 SCV000788886 uncertain significance Ataxia-telangiectasia syndrome 2016-12-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120134 SCV000916550 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: ATM c.3630G>A (p.Met1210Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 282764 control chromosomes (in gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (2.8e-05 vs 0.001), allowing no conclusion about variant significance. The c.3630G>A variant has been reported in the literature in an individual affected with Breast Cancer (Sommer 2003, Tavtigian 2009), but also was found in healthy controls (Bodian 2014), thus these reports do not provide unequivocal conclusions about an association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000120134 SCV000084273 not provided not specified 2013-09-19 no assertion provided reference population

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