ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6200C>A (p.Ala2067Asp) (rs397514577)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166627 SCV000217431 pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing The p.A2067D pathogenic mutation (also known as c.6200C>A), located in coding exon 42 of the ATM gene, results from a C to A substitution at nucleotide position 6200. The alanine at codon 2067 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in two individuals/families with ataxia-telangiectasia (Sandoval N et a. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Dawson AJ et al. Am. J. Med. Genet. 2015 Aug;167A(8):1937-9). This alteration has also been shown to segregate with primary-appearing dystonia in homozygous individuals from three Canadian Mennonite families (Saunders-Pullman R et al. Neurology. 2012 Feb; 78(9):649-57). Additionally, functional assays demonstrated that this alteration results in reduced protein expression, absent autophosphorylation, and diminished transphorphylation of downstream ATM targets (Nakamura K et al. Mol Genet Genomic Med. 2014 Jul; 2(4):332-40). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, this variant is unlikely to be causative of classical ataxia-telangiectasia; however, it may be associated with dystonia and may lead to increased risk of developing ATM-related cancer. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000258124 SCV000547142 pathogenic Ataxia-telangiectasia syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2067 of the ATM protein (p.Ala2067Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with ataxia-telangiectasia (A-T) in three families (PMID: 22345219) where all affected individuals were homozygous for this variant. This sequence change has also been observed in unrelated individuals with A-T (PMID: 9887333, 25914063, Invitae). ClinVar contains an entry for this variant (Variation ID: 39749). Experimental studies have shown that this missense change leads to diminished protein expression and reduced enzyme activity in cells derived from patients homozygous for this variant and in cell lines expressing protein harboring the p.Ala2067Asp variant (PMID: 25077176). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000258124 SCV000800774 pathogenic Ataxia-telangiectasia syndrome 2017-06-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762825 SCV000893183 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166627 SCV000903208 likely pathogenic Hereditary cancer-predisposing syndrome 2020-12-03 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 2067 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with typical or mild ataxia telangiectasia (PMID: 9887333, 22345219, 25037873, 25077176, 25914063). Lymphoblastoid cells isolated from the homozygous carriers have shown absent to trace levels of ATM protein, reduced ATM kinase activity, and increased sensitivity to radiation, indicating reduced capacity to repair DNA damage (PMID: 22345219, 25077176). This variant has also been reported in individuals affected with breast cancer (PMID: 20305132, 26898890). This variant has been identified in 1/251316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268054 SCV001446662 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001268054 SCV001502096 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
OMIM RCV000032965 SCV000056740 pathogenic Ataxia-telangiectasia variant 2012-02-28 no assertion criteria provided literature only
GeneReviews RCV000258124 SCV000328268 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356731 SCV001551978 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Ala2067Asp variant was identified in 64 of 23034 proband chromosomes (frequency: 0.003) from individuals or families with atypical or “variant-Ataxia Telangiectasia”, breast and ovarian cancer and was not identified in 7976 control chromosomes from healthy individuals (Sandoval 1999, Saunders-Pullman 2012, Lu 2019). The variant was identified in dbSNP (rs397514577) as “with pathogenic allele”, ClinVar (interpreted as pathogenic by Invitae and 4 others, likely pathogenic by Color and 1 other) and LOVD 3.0 (observed 11x). The variant was identified in control databases in 1 of 246,124 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111,648 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The homozygous variant was observed in 3 families with 12 affected people. Patients presented with a variant form of Ataxia Telangiectasia, a milder form of the disease, and 8 of the 12 homozygous carriers had a malignancy later in life including stomach, prostate, myeloid leukemia and lymphoma (Saunders-Pullman 2012, Nakamura 2014). Of the 10 carriers, six were homozygous and 4 were compound heterozygotes with ATM pathogenic variants (p.Arg1898*, p.Glu1978* and p.Val1268*) and segregated in trans (Nakamura 2014). Western blot of lymphoblastoid cell lines derived from these patients had decreased expression of ATM protein. Additionally, site directed mutagenesis experiments that introduced the homozygous variant had low levels of ATM protein in vitro. The presence of the variant also decreased kinase activity by ATM (Nakamura 2014). The p.Ala2067 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Ala2067Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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