Submissions for variant NM_000051.4(ATM):c.2836A>G (p.Met946Val)

gnomAD frequency: 0.00004  dbSNP: rs587781992

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130397	SCV000185256	likely benign	Hereditary cancer-predisposing syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000168097	SCV000218753	likely benign	Ataxia-telangiectasia syndrome	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000485729	SCV000568002	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Hauke et al., 2018); This variant is associated with the following publications: (PMID: 29522266)
Fulgent Genetics, Fulgent Genetics	RCV000515251	SCV000611353	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130397	SCV000902852	likely benign	Hereditary cancer-predisposing syndrome	2016-05-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779792	SCV000916594	uncertain significance	not specified	2021-08-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2836A>G (p.Met946Val) results in a conservative amino acid change located in the PIK-related kinase - FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2836A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467147	SCV004210205	uncertain significance	Familial cancer of breast	2023-07-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492600	SCV004240480	uncertain significance	Breast and/or ovarian cancer	2022-09-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000168097	SCV001452054	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356743	SCV001551996	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Met946Val variant was identified in 1 of 11178 proband chromosomes (frequency: 0.00009) from German individuals or families with BRCA1/2 negative breast or ovarian cancer (Hauke 2018). The variant was also identified in dbSNP (ID: rs587781992) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and Fulgent Genetics (Fulgent Genetics)) and not identified in LOVD 3.0 database. The variant was identified in control databases in 4 of 277036 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24038 chromosomes (freq: 0.00004) and European Non-Finnish in 3 of 126682 chromosomes (freq: 0.00002), while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Met946 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The p.Met946Val variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.