Submissions for variant NM_000051.4(ATM):c.387del (p.Asp130fs)

dbSNP: rs745642834

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003469205	SCV004565377	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.387del (p.Asp130IlefsTer23) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in two individuals with Ataxia-Telangiectasia (PMID: 26896183, 30549301), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM3, PM5_Supporting).
GeneDx	RCV000255124	SCV000322627	pathogenic	not provided	2023-12-27	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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26556299, 30549301, 31069529, 33084842, 29922827, 32255556, 26896183)
Color Diagnostics, LLC DBA Color Health	RCV000580692	SCV000682166	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-08	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251256 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.
Ambry Genetics	RCV000580692	SCV001182947	pathogenic	Hereditary cancer-predisposing syndrome	2018-06-08	criteria provided, single submitter	clinical testing	The c.387delA pathogenic mutation, located in coding exon 4 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 387, causing a translational frameshift with a predicted alternate stop codon (p.D130Ifs*23). 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	RCV001206728	SCV001378050	pathogenic	Ataxia-telangiectasia syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp130Ilefs*23) 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 present in population databases (rs745642834, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ATM-related conditions (PMID: 26556299, 30549301). ClinVar contains an entry for this variant (Variation ID: 265634). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001206728	SCV002521195	pathogenic	Ataxia-telangiectasia syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000265634 / PMID: 26556299). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003469205	SCV004210337	pathogenic	Familial cancer of breast	2023-05-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469205	SCV004933464	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.