Submissions for variant NM_000051.4(ATM):c.6452+2T>C

dbSNP: rs1064795006

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481420	SCV000570385	uncertain significance	not provided	2016-05-23	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6452+2T>C or IVS44+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 44 of the ATM gene. This particular variant has not, to our knowledge, been published in the literature. Although this variant destroys a canonical splice donor site and is predicted to cause abnormal splicing of exon 44, the skipping of exon 44 is predicted to be an in-frame event. Since the rest of the protein is expected to be translated and the loss of this one exon may or may not inhibit proper protein functioning, the clinical significance of ATM c.6452+2T>C remains unclear at this time. Based on the currently available information, we consider ATM c.6452+2T>C to be a variant of uncertain significance.
Counsyl	RCV000675168	SCV000800788	likely pathogenic	Ataxia-telangiectasia syndrome	2017-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675168	SCV001623270	likely pathogenic	Ataxia-telangiectasia syndrome	2021-05-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6452+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248184 control chromosomes. To our knowledge, no occurrence of c.6452+2T>C in individuals affected with Ataxia-Telangiectasia/Breast cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.