Submissions for variant NM_000051.4(ATM):c.3993G>C (p.Gln1331His)

dbSNP: rs863224566

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206293	SCV000262350	uncertain significance	Ataxia-telangiectasia syndrome	2023-08-06	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 221142). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1331 of the ATM protein (p.Gln1331His). This variant also falls at the last nucleotide of exon 26, which is part of the consensus splice site for this exon.
Ambry Genetics	RCV000221742	SCV000273958	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	The c.3993G>C variant (also known as p.Q1331H), located in coding exon 25 of the ATM gene, results from a G to C substitution at nucleotide position 3993. This change occurs in the last base pair of coding exon 25, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.3993+1G>A ), has been shown to have a similar impact on splicing (Ambry internal data) and has has been described in several ataxia-telangiectasia families (Laake K et al. Hum. Mutat. 2000; 16:232-46; Mitui M et al. Hum. Mutat. 2003; 22:43-50). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000479019	SCV000569334	likely pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to result in abnormal splicing (External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Observed in individuals with breast cancer and absent in unaffected controls (PMID: 28779002); This variant is associated with the following publications: (PMID: 28055970, 22941188, 26010451, 28779002)
Baylor Genetics	RCV003468966	SCV004212154	uncertain significance	Familial cancer of breast	2022-12-07	criteria provided, single submitter	clinical testing