Submissions for variant NM_000051.4(ATM):c.1303T>C (p.Leu435=)

gnomAD frequency: 0.00001  dbSNP: rs748469311

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165265	SCV000215981	likely benign	Hereditary cancer-predisposing syndrome	2014-07-30	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.
PreventionGenetics, part of Exact Sciences	RCV000252163	SCV000301651	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000470029	SCV000558436	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165265	SCV000681965	likely benign	Hereditary cancer-predisposing syndrome	2016-06-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001675648	SCV001894373	benign	not provided	2015-05-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165265	SCV002530265	likely benign	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316039	SCV004017369	likely benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316039	SCV005084521	benign	Familial cancer of breast	2024-04-26	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	RCV001355218	SCV001550038	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu435L= variant was not identified in the literature nor was it identified in the LOVD 3.0 databases. The variant was identified in dbSNP (rs748469311) as “with likely benign allele” and ClinVar (interpreted as "likely benign" Invitae and 3 others). The variant was identified in control databases in 8 of 245856 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5476 chromosomes (freq: 0.0004), European in 4 of 111,514 chromosomes (freq: 0.00004), and South Asian in 2 of 30778 chromosomes (freq: 0.00007). The variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian and Finnish populations. The p.Leu435= 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-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.