Submissions for variant NM_000051.4(ATM):c.6604T>G (p.Tyr2202Asp)

gnomAD frequency: 0.00003  dbSNP: rs730881311

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766519	SCV000209630	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and other cancers (Mansouri et al., 2013; Lu et al., 2015; Hauke et al., 2018); This variant is associated with the following publications: (PMID: 24172824, 27720647, 29522266, 26689913, 33436325, 23532176)
Ambry Genetics	RCV000159641	SCV000214861	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	The p.Y2202D variant (also known as c.6604T>G), located in coding exon 45 of the ATM gene, results from a T to G substitution at nucleotide position 6604. The tyrosine at codon 2202 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has been reported in 3/13087 breast cancer cases and 2/5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000199822	SCV000254133	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2202 of the ATM protein (p.Tyr2202Asp). This variant is present in population databases (rs730881311, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or head and neck squamous carcinoma (PMID: 26689913, 29522266). ClinVar contains an entry for this variant (Variation ID: 181882). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Genetic Services Laboratory, University of Chicago	RCV000212047	SCV000593506	uncertain significance	not specified	2016-10-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159641	SCV000682356	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with aspartic acid at codon 2202 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 29522266) and head and neck squamous cell carcinoma (PMID: 26689913). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 8/53453 controls (OR=0.553, 95%CI 0.181 to 1.689, p-value=0.406; PMID: 33471991). This variant has been identified in 3/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000764938	SCV000896110	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212047	SCV000916575	uncertain significance	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6604T>G (p.Tyr2202Asp) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121096 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (1.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.6604T>G, has been reported in the literature in individuals affected with chronic lymphocytic leukemia and head and neck squamous cell carcinoma (Mansouri 2014, Lu 2015), however it also was found in women, older than age 70 years who have never had cancer (in the FLOSSIES database). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798542	SCV002042767	uncertain significance	Breast and/or ovarian cancer	2020-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462068	SCV004215523	uncertain significance	Familial cancer of breast	2023-05-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212047	SCV004242538	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000766519	SCV001553202	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Tyr2202Asp variant was identified by Mansouri (2013) in an individual with chronic myelogenous leukemia. The variant was also identified in dbSNP (ID: rs730881311) as “With Uncertain significance allele”, and in ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, University of Chicago, and Color Genomics). The variant was not identified in the Cosmic, MutDB, LOVD 3.0, or ATM-LOVD database. The variant was identified in control databases in 3 of 245856 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15300 chromosomes (freq: 0.00007), European (Non-Finnish) in 2 of 111502 chromosomes (freq: 0.000018); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Tyr2202 residue is conserved in mammals but not in more distantly related organisms, and 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000199822	SCV002084452	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-19	no assertion criteria provided	clinical testing