Submissions for variant NM_000051.4(ATM):c.3154-4G>A

dbSNP: rs199543313

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131267	SCV000186235	likely benign	Hereditary cancer-predisposing syndrome	2018-09-27	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	RCV000211993	SCV000209596	benign	not specified	2014-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079697	SCV000252955	benign	Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131267	SCV000537432	likely benign	Hereditary cancer-predisposing syndrome	2015-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211993	SCV000694250	likely benign	not specified	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3154-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 1613642 control chromosomes in the gnomAD database, including 4 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00023 vs 0.004), however the presence of homozygotes in controls suggest the variant could be benign. c.3154-4G>A has been reported in the literature as a VUS in settings of multigene panel testing among in individuals undergoing testing for Lynch and/or associated cancers (example, Yurgelun_2015, Grant_2015, Tung_2014, Pereira_2022). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.1670T>G, p.Leu557X), 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: 25479140, 25186627, 25980754, 35980532, 34299313, 32658311). ClinVar contains an entry for this variant (Variation ID: 142254). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV002292436	SCV001148413	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ATM: BP4
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002292436	SCV002010833	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211993	SCV002067136	likely benign	not specified	2019-07-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131267	SCV002533587	likely benign	Hereditary cancer-predisposing syndrome	2021-06-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211993	SCV002760549	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149907	SCV003837725	uncertain significance	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315904	SCV004016520	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002292436	SCV004220946	benign	not provided	2018-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315904	SCV005083898	benign	Familial cancer of breast	2024-05-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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].
Athena Diagnostics	RCV000211993	SCV005621036	benign	not specified	2024-01-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001079697	SCV001462133	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358310	SCV001554010	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.3154-4G>A variant was identified in 2 of 3100 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch Syndrome and pancreatic cancer (Yurgelun 2015, Grant 2015). The variant was identified in dbSNP (rs199543313) as “with uncertain significance allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; as benign by GeneDx; and as uncertain significance by Integrated Genetics) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 53 of 282,472 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7206 chromosomes (freq: 0.0004), European in 36 of 128962 chromosomes (freq: 0.0003), Ashkenazi Jewish in 2 of 10,358 chromosomes (freq: 0.0002), Latino in 6 of 35,420 chromosomes (freq: 0.0002), South Asian in 4 of 30,602 chromosomes (freq: 0.0001), and African in 2 of 24,920 chromosomes (freq: 0.00008), while it was not observed in the East Asian or Finnish populations. The c.3154-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, nor does it affect positions -3 and -5 to -12, which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, c.3154-4G>A is a non-highly conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.