Submissions for variant NM_000051.4(ATM):c.3300G>A (p.Thr1100=)

gnomAD frequency: 0.00003  dbSNP: rs587780621

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122841	SCV000166099	likely benign	Ataxia-telangiectasia syndrome	2025-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162548	SCV000212956	likely benign	Hereditary cancer-predisposing syndrome	2014-09-11	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.
Color Diagnostics, LLC DBA Color Health	RCV000162548	SCV000682116	likely benign	Hereditary cancer-predisposing syndrome	2015-07-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779771	SCV000916561	likely benign	not specified	2020-12-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122841	SCV001260524	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	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.
GeneDx	RCV001657770	SCV001874176	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162548	SCV002535879	likely benign	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001657770	SCV004700834	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Myriad Genetics, Inc.	RCV004589599	SCV005084530	benign	Familial cancer of breast	2024-05-14	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356792	SCV001552057	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr1100= variant was identified in 5 of 26,174 proband chromosomes (frequency: 0.0002) from individuals with breast cancer and was present in 2 of 10,976 control chromosomes (frequency: 0.0002) from healthy individuals (Decker 2017). The variant was identified in dbSNP (rs587780621) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; and as uncertain significance by Integrated Genetics). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 8 of 246,900 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 110,850 chromosomes (freq: 0.00007), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Thr1100= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 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.