Submissions for variant NM_000051.4(ATM):c.5890A>G (p.Lys1964Glu)

gnomAD frequency: 0.00011  dbSNP: rs201963507

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130965	SCV000185880	likely benign	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000212034	SCV000209753	uncertain significance	not specified	2017-09-21	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5890A>G at the cDNA level, p.Lys1964Glu (K1964E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). ATM Lys1964Glu has been observed in at least two individuals with breast and/or ovarian cancer, and was absent from unaffected controls (Thorstenson 2003, Tavtigian 2009, Goldgar 2011). This variant was also reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). ATM Lys1964Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys1964Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Lys1964Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197688	SCV000254126	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130965	SCV000537568	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1964 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. In a large international case-control study, this variant was reported in 12/60454 breast cancer cases and 13/53448 controls (OR=0.816, 95%CI 0.372 to 1.789, p-value=0.69; PMID: 33471991). This variant has been reported in other individuals affected with breast cancer (PMID: 19781682, 21787400, 23555315), ovarian cancer (PMID: 30651582, 36521553), suspected Lynch syndrome (PMID: 25980754), and advanced cancer (PMID: 28873162). This variant has been identified in 26/282432 chromosomes in the general population, including 1 homozygote, by the Genome Aggregation Database (gnomAD) and in an individual age 70 or older without cancer (https://whi.color.com/variant/11-108181014-A-G). 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	RCV000515322	SCV000611368	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212034	SCV000694309	uncertain significance	not specified	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5890A>G (p.Lys1964Glu) results in a conservative amino acid change located in the PIK-related kinase domain of 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 9.8e-05 in 255536 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (9.8e-05 vs 0.001), allowing no conclusion about variant significance. c.5890A>G has been reported in the literature in individuals affected with different types of cancer or dysnotia (e.g.Tavtigian_2009, Yurgelun_2015, Pogoda_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.6302delA, p.Asn2101Metfs, Moradian_2021), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21787400, 23555315, 33436325, 30651582, 33558524, 26837699, 29659569, 31920950, 19781682, 12810666, 31159747, 26787654, 25980754, 35264596). Based on the evidence outlined above, the variant was classified as VUS possibly benign.
GeneKor MSA	RCV000130965	SCV000821862	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492611	SCV000838561	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000197688	SCV001262767	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000197688	SCV002012409	uncertain significance	Ataxia-telangiectasia syndrome	2021-09-29	criteria provided, single submitter	clinical testing	The ATM c.5890A>G (p.Lys1964Glu) missense change has a maximum frequency of 0.017% in gnomAD v2.1.1, including one individual homozygous for the variant (https://gnomad.broadinstitute.org/variant/11-108181014-A-G?dataset=gnomad_r2_1). This variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 12810666, 23555315, 28779002, 29522266, 31159747, 31206626, 32658311), endometrial cancer (PMID: 32885271), suspected Lynch syndrome (PMID: 25980754, 32885271), and dystonia (PMID: 31920950). A small case control study suggested that this variant is associated with breast cancer (PMID: 23555315), however other studies have observed this variant in relatively equal numbers of cases and controls (PMID: 31206626, 32658311). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/11-108181014-A-G). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been observed in a case of pediatric AML in which the variant allele was lost in the tumor (internal data). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
MGZ Medical Genetics Center	RCV002288644	SCV002581847	uncertain significance	Familial cancer of breast	2022-08-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212034	SCV004024329	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003390822	SCV004133262	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: BP4
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483502	SCV004228283	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-14	criteria provided, single submitter	curation	1xhomozygot in gnomAD (others). According to the ACMG standard criteria we chose this criterium: BP4 (supporting benign): ClinGen Interpretation Guidelines for ATM Version 1.1: BP4 (REVEL score <.249)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492610	SCV004239361	uncertain significance	Breast and/or ovarian cancer	2022-07-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288644	SCV005084001	likely benign	Familial cancer of breast	2024-05-24	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].
Center of Medical Genetics and Primary Health Care	RCV001269498	SCV001449155	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357333	SCV001552776	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The ATM p.Lys1964Glu variant was identified in 4 of 13262 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer or Lynch syndrome and was not identified in 7630 control chromosomes from healthy individuals (Goldgar 2011, Tavtigian 2009, Thorstenson 2003, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs201963507 as "With Pathogenic, Uncertain significance allele"), ClinVar (1x as likely benign by Invitae and 5x as uncertain significance by Ambry Genetics, GeneDx, Color Genomics, Fulgent Genetics, and Integrated Genetics/Laboratory Corporation of America), and Cosmic (3x in Haematopoietic and lymphoid tissue). The variant was not identified in the COGR, MutDB, or LOVD 3.0 database. The variant was identified in control databases in 25 of 276812 chromosomes (1 homozygous) at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 7 of 34384 chromosomes (1 homozygous, freq: 0.0002), European in 12 of 126464 chromosomes (freq: 0.0001), and South Asian in 3 of 30772 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Lys1964 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004551259	SCV004115941	uncertain significance	ATM-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The ATM c.5890A>G variant is predicted to result in the amino acid substitution p.Lys1964Glu. This variant has been reported in individuals with breast/ovarian cancer (Thorstenson et al. 2003. PubMed ID: 12810666; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A2, Krivokuca et al. 2019. PubMed ID: 30651582; Table S1, Moradian et al. 2021. PubMed ID: 33558524), prostate cancer (Table S3, Darst et al. 2021. PubMed ID: 32853339; Table S4, Karlsson et al. 2021. PubMed ID: 33436325), chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), and those undergoing Lynch syndrome testing (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). In at least one individual a pathogenic variant was also identified in BRCA2 (Table S1, Moradian et al. 2021. PubMed ID: 33558524). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity of uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142126/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.