Submissions for variant NM_000051.4(ATM):c.876G>A (p.Pro292=)

gnomAD frequency: 0.00001  dbSNP: rs755860432

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220083	SCV000273405	likely benign	Hereditary cancer-predisposing syndrome	2015-12-12	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.
Invitae	RCV000228448	SCV000283090	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000434328	SCV000512135	benign	not specified	2015-03-23	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.
Color Diagnostics, LLC DBA Color Health	RCV000220083	SCV000682513	likely benign	Hereditary cancer-predisposing syndrome	2017-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000434328	SCV004100107	likely benign	not specified	2023-09-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001356035	SCV004133235	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Myriad Genetics, Inc.	RCV004589920	SCV005084040	benign	Familial cancer of breast	2024-04-23	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	RCV001356035	SCV001551089	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Pro292= variant was identified in the literature however the frequency of this variant in an affected population was not provided (Decker 2017). The variant was also identified in the following databases: dbSNP (ID: rs755860432) as "With Likely benign allele", ClinVar (2x likely benign, 1x benign), and Clinvitae (2x likely benign, 1x benign). The variant was not identified in Cosmic, MutDB, or LOVD 3.0. The variant was identified in control databases in 13 of 243644 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 5 of 33486 chromosomes (freq: 0.0001), European in 1 of 111146 chromosomes (freq: 0.000009), Ashkenazi Jewish in 2 of 9828 chromosomes (freq: 0.0002), East Asian in 1 of 17192 chromosomes (freq: 0.00006), and South Asian in 4 of 30758 chromosomes (freq: 0.0001). The variant was not observed in the African, Other, or Finnish populations. The p.Pro292 residue is conserved across mammals and other organisms, however it 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, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In our lab this variant was observed with a co-occurring pathogenic BRCA1 variant c.5161C>T, increasing the likelihood that the p.Pro292= variant does not have clinical significance. 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.