Submissions for variant NM_000051.4(ATM):c.3576G>T (p.Lys1192Asn)

dbSNP: rs587776551

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583698	SCV000687489	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the last nucleotide of exon 24 of the ATM gene and replaces lysine with asparagine at codon 1192 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant leads to the skipping of exon 24 in the RNA transcript, which is expected to result in an in-frame deletion of 58 amino acids of the ATM protein (communication with an external laboratory). Moreover, RNA studies have reported that a different variant affecting the same nucleotide position, c.3576G>A, also caused abnormal RNA splicing (PMID: 9887333, 21965147). While to our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature, the similar variant, c.3576G>A, has been reported in individuals affected with ataxia-telangiectasia and breast cancer and is considered to be disease-causing (ClinVar variation ID: 3035). It suggests that this nucleotide position is clinically significant. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241162	SCV001414159	likely pathogenic	Ataxia-telangiectasia syndrome	2022-10-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1192 of the ATM protein (p.Lys1192Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant has not been reported in the literature in individuals affected with ATM-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.3576G nucleotide in the ATM gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8845835, 9887333, 17124347, 19691550, 22071889). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 24, also known as exon 23, but is expected to preserve the integrity of the reading-frame (external communication). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 490539).
Ambry Genetics	RCV000583698	SCV003866515	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The c.3576G>T variant (also known as p.K1192N), located in coding exon 23 of the ATM gene, results from a G to T substitution at nucleotide position 3576. The amino acid change results in lysine to asparagine at codon 1192, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004024633	SCV004931279	likely pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9887333]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8698354, Myriad internal data].