Submissions for variant NM_000051.4(ATM):c.8850+5dup

dbSNP: rs1400626849

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001524952	SCV001734935	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This variant inserts one nucleotide at the +5 position of intron 61 of the ATM gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251236 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001872062	SCV002291074	uncertain significance	Ataxia-telangiectasia syndrome	2023-07-10	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change falls in intron 61 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with breast cancer (PMID: 32658311). ClinVar contains an entry for this variant (Variation ID: 1171683). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Ambry Genetics	RCV001524952	SCV002682742	likely benign	Hereditary cancer-predisposing syndrome	2022-03-09	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155415	SCV003844582	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8850+5dupA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one in-silico tool (TraP, Transcript-inferred Pathogenicity, Gelfman_2017) predicts this intron variant to be benign. The variant allele was found at a frequency of 1.2e-05 in 252216 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8850+5dupA has been reported in the literature in at least one individual affected with Breast Cancer (Akcay_2021). The report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.