ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

ATM: BP4

Variant summary: ATM c.3154-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 251096 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0002 vs 0.004), allowing no conclusion about variant significance c.3154-4G>A has been reported in the literature as a VUS in settings of multigene panel testing among in individuals undergoing testing for Lynch and/or associated cancers (example, Yurgelun_2015, Grant_2015, Tung_2014, Pereira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia (AT) and/or AT-associated cancers. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.1670T>G, p.Leu557X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25479140, 25186627, 25980754, 35980532, 34299313, 32658311). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments and a majority consensus leaning towards a likely benign/benign outcome (n=9) (VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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.

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The ATM c.3154-4G>A variant was identified in 2 of 3100 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch Syndrome and pancreatic cancer (Yurgelun 2015, Grant 2015). The variant was identified in dbSNP (rs199543313) as “with uncertain significance allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; as benign by GeneDx; and as uncertain significance by Integrated Genetics) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 53 of 282,472 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7206 chromosomes (freq: 0.0004), European in 36 of 128962 chromosomes (freq: 0.0003), Ashkenazi Jewish in 2 of 10,358 chromosomes (freq: 0.0002), Latino in 6 of 35,420 chromosomes (freq: 0.0002), South Asian in 4 of 30,602 chromosomes (freq: 0.0001), and African in 2 of 24,920 chromosomes (freq: 0.00008), while it was not observed in the East Asian or Finnish populations. The c.3154-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, nor does it affect positions -3 and -5 to -12, which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, c.3154-4G>A is a non-highly conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.