Submissions for variant NM_000051.4(ATM):c.6228del (p.Leu2077fs)

dbSNP: rs786203008

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166124	SCV000216895	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	The c.6228delT pathogenic mutation, located in coding exon 42 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 6228, causing a translational frameshift with a predicted alternate stop codon (p.L2077Ffs*5). This pathogenic mutation has been reported in an individual with ataxia-telangiectasia (Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7). It has also been reported in an individual with a personal history of breast and pancreatic cancer and family history of thyroid, colon and prostate cancer (Frey MK et al. Gynecol. Oncol. 2015 Nov;139(2):211-5). The c.6228delT mutation has been detected in a patient with pancreatic cancer and a family history of breast cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205743	SCV000260167	pathogenic	Ataxia-telangiectasia syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2077Phefs*5) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10817650). ClinVar contains an entry for this variant (Variation ID: 186516). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236779	SCV000292791	pathogenic	not provided	2021-05-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26296696, 31285527, 10817650, 27304073, 28767289, 28495237, 29439820, 32445285)
Genetic Services Laboratory, University of Chicago	RCV000503030	SCV000593511	pathogenic	Breast cancer, susceptibility to	2017-04-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166124	SCV000682314	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 43 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 10817650) and in individuals affected with breast cancer, pancreatic cancer, and melanoma (PMID: 26296696, 28495237, 28767289, 34262154, 36091166). This variant has also been identified in 1/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000236779	SCV000703277	pathogenic	not provided	2018-01-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000205743	SCV001365993	pathogenic	Ataxia-telangiectasia syndrome	2019-03-22	criteria provided, single submitter	clinical testing	The p.Leu2077fs variant in ATM has been reported in one individual with ataxia-telangiectasia; however a second variant in the ATM gene was not identified (Li 2000). In addition, the variant was detected in one patient with a history of breast and pancreatic cancer, and a family history of thyroid, colon and prostate cancer (Frey 2015). The variant has also been reported in the ClinVar database (Variation ID# 186516), and was absent from large population studies. The p.Leu2077fs variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2077 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for ataxia-telangiectasia in an autosomal recessive manner. Additionally, carriers of pathogenic ATM variants may be at increased risk for developing cancers (Gatti 2016, van Os 2016). ACMG/AMP criteria applied: PVS1; PM2; PS4_supporting.
Baylor Genetics	RCV003468772	SCV004212031	pathogenic	Familial cancer of breast	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468772	SCV004932168	pathogenic	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000205743	SCV001457410	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing