ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2250G>A (p.Lys750=) (rs1137887)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235101 SCV000149058 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.2250G>A at the DNA level. Although the variant is silent at the coding level, preserving a Lysine at codon 750, it disrupts the nearby natural splice donor site and causes abnormal splicing. ATM c.2250G>A has been shown to cause skipping of exon 14, also known as exon 16 using alternate nomenclature, and reduced ATM protein expression levels (Sandoval 1999, Teraoka 1999, Prodosmo 2013, Shirts 2016). This variant has been observed in the homozygous or compound heterozygous state in multiple patients with Ataxia-telangiectasia (Byrd 1996, Laake 2000, Buzin 2003, Cavalieri 2006, Chessa 2009, Podralska 2014, Milligan 2016, Leuzzi 2018). ATM c.2250G>A has also been reported in the heterozygous state individuals with a personal and/or family history of breast, pancreatic, colon, or prostate cancer (Grana 2011, Castera 2014, Shirts 2016, Barnes 2017, Decker 2017, Goidescu 2018). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, we consider ATM c.2250G>A to be a pathogenic variant.
Invitae RCV000003185 SCV000166090 pathogenic Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change affects codon 750 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. It also falls at the last nucleotide of exon 14 of the ATM coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs1137887, ExAC 0.002%). This variant has been observed in individuals and families affected with ataxia-telangiectasia (PMID: 9463314, 10980530, 9887333, 10330348, 19691550). Exon 14 is also referred to as exon 16 in the literature. ClinVar contains an entry for this variant (Variation ID: 3044). Experimental studies evaluating the splicing effect of this variant reported that it resulted in skipping of exon 14 (c.2125_2250del, p.Ile709_Lys750del) from the ATM mRNA (PMID: 9887333, 10330348). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115149 SCV000183940 pathogenic Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon
University of Washington Department of Laboratory Medicine, University of Washington RCV000003185 SCV000266148 pathogenic Ataxia-telangiectasia syndrome 2017-07-11 criteria provided, single submitter clinical testing
Counsyl RCV000003185 SCV000486402 pathogenic Ataxia-telangiectasia syndrome 2016-05-27 criteria provided, single submitter clinical testing
Color RCV000115149 SCV000682042 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115149 SCV000821696 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant occurs at the last base of exon 14, a position that is highly conserved in the human and other genomes. Although it does not result in an amino acid substitution, it has been demonstrated to affect splicing of the mRNA, specifically in frame skipping of the entire exon 14 (c.2125_2250del, p.(Ile709_Lys750del) (PMID: 10330348). This variant is listed in population databases at a very low frequency (rs1137887, ExAC <0.01%) and has been described in the international bibliography in individuals and families affected with Ataxia Telangiectasia (A-T) (PMID: 19691550, 10980530, 10330348 ). The mutation database ClinVar contains entries for this variant (Variation ID:3044).
Athena Diagnostics Inc RCV000235101 SCV000840925 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762817 SCV000893175 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003185 SCV000918520 pathogenic Ataxia-telangiectasia syndrome 2018-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.2250G>A (p.Lys750Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 4.5e-05 in 245598 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.5e-05 vs 0.004), allowing no conclusion about variant significance. c.2250G>A has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia. These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All labs classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003185 SCV000023343 pathogenic Ataxia-telangiectasia syndrome 2002-04-01 no assertion criteria provided literature only
King Laboratory,University of Washington RCV001171385 SCV001251283 pathogenic Familial cancer of breast 2019-09-01 no assertion criteria provided research

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