Submissions for variant NM_000051.4(ATM):c.4631A>G (p.Tyr1544Cys)

gnomAD frequency: 0.00001  dbSNP: rs779718362

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236361	SCV000292922	uncertain significance	not provided	2018-03-13	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4631A>G at the cDNA level, p.Tyr1544Cys (Y1544C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant has been observed in individuals with breast or lung cancer, but has also been observed in a healthy control subject (Lu 2015, Decker 2017). ATM Tyr1544Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr1544Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471874	SCV000546904	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1544 of the ATM protein (p.Tyr1544Cys). This variant is present in population databases (rs779718362, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or lung cancer (PMID: 25186627, 26689913, 30426508). ClinVar contains an entry for this variant (Variation ID: 245791). 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.
Ambry Genetics	RCV000566756	SCV000660447	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	The p.Y1544C variant (also known as c.4631A>G), located in coding exon 30 of the ATM gene, results from an A to G substitution at nucleotide position 4631. The tyrosine at codon 1544 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). In another study, This variant was identified in 1/272 Norwegian breast cancer patients and was not observed in 95 cancer-free Norwegian controls or 95 American breast cancer patients (Edvardsen H et al. Radiat Oncol, 2007 Jul;2:25). This alteration was also detected on a 25-gene panel test in a woman diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566756	SCV000682216	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1544 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 17623063, 25186627, 28779002, 29522266, 33471991). However, in two large breast cancer case-control studies, this variant has also been identified in control groups (PMID: 28779002, 33471991). In a case-control study conducted in the UK, this variant was reported in 1/13087 breast cancer cases and 1/5488 controls (PMID: 28779002). In an international case-control meta-analysis, this variant was reported in 2/60464 breast cancer cases and 11/53450 controls (OR=0.161, 95%CI 0.036 to 0.725, p-value=0.009; PMID: 33471991). This variant has also been reported in individuals affected with caecal adenocarcinoma (PMID: 3638722) and metastatic prostate cancer (PMID: 36979741). This variant has been identified in 8/240752 chromosomes in the general population by the Genome Aggregation Database (gnomAD), all of which were found in individuals of European (non-Finnish) ancestry (8/109334 chromosomes). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780886	SCV000918515	uncertain significance	not specified	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4631A>G (p.Tyr1544Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 240942 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4631A>G has been reported in the literature in individuals affected with breast cancer and also in individuals undergoing hereditary cancer testing (Edvardsen_2007, Tung_2014, Schubert_2019, Mu_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrence with another pathogenic variant has been reported (internal sample; NBN c.657_661delACAAA, p.Lys219AsnfsX16) for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236361	SCV001473726	uncertain significance	not provided	2019-11-24	criteria provided, single submitter	clinical testing	The ATM c.4631A>G; p.Tyr1544Cys variant (rs779718362) is reported in the literature in individuals with breast cancer (Edvardsen 2007, Tung 2015), and is also reported in ClinVar (Variation ID: 245791). This variant is found in the general population with an overall allele frequency of 0.003% (8/240752 alleles) in the Genome Aggregation Database. The tyrosine at codon 1544 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Edvardsen H et al. Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. Radiat Oncol. 2007 Jul 10;2:25. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236361	SCV002010813	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000780886	SCV002068439	uncertain significance	not specified	2018-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469180	SCV004207088	uncertain significance	Familial cancer of breast	2023-10-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469180	SCV005084017	likely benign	Familial cancer of breast	2024-05-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000471874	SCV001462333	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000236361	SCV001906137	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236361	SCV001954229	uncertain significance	not provided		no assertion criteria provided	clinical testing