Submissions for variant NM_000051.4(ATM):c.2220A>G (p.Ala740=)

gnomAD frequency: 0.00005  dbSNP: rs56353517

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163515	SCV000214073	likely benign	Hereditary cancer-predisposing syndrome	2015-03-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232692	SCV000282891	benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163515	SCV000682041	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000232692	SCV000790162	likely benign	Ataxia-telangiectasia syndrome	2017-03-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000232692	SCV001260418	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192849	SCV001361261	likely benign	not specified	2019-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001711329	SCV001945464	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315999	SCV004017225	likely benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315999	SCV005083967	benign	Familial cancer of breast	2024-05-07	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192849	SCV005090092	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356556	SCV001551761	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ala740= variant was identified in 1 of 14102 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and was identified in 5 of 24980 control chromosomes (frequency: 0.0002) from healthy men individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs56353517) as "With Likely benign allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, Color and Counsyl), and in LOVD 3.0 (2x). The variant was identified in control databases in 25 of 277006 chromosomes (1 homozygous) at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 25 of 18816 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ala740= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.