ClinVar Genomic variation as it relates to human health

Observed in individuals with breast cancer, colon cancer, other cancers, and/or colon polyps, but also in unaffected controls (PMID: 16832357, 19781682, 26689913, 25980754, 28779002, 27978560, 28135145, 29596542, 31882575, 36243179); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 26689913, 28135145, 19781682, 27978560, 28779002, 22529920, 25980754, 16832357, 29596542, 31882575, 33471991, 29641532, 36243179, 35982160)

Variant summary: ATM c.2804C>T (p.Thr935Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 282986 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (6.4e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.2804C>T, has been reported in the literature in individuals affected with colorectal cancer (Yurgelun_2015, Yurgelun_JAMAOnc_2016) but also in controls (Tavtigian_2009, Renwick_2006). These reports do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x3, likely benign x1). Based on the evidence outlined above, the variant was classified as uncertain significance.

The ATM c.2804C>T (p.Thr935Met) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast or colorectal cancer (PMID: 25980754, 27978560, 28135145, 28779002, 31882575, 33471991). This variant has been reported in 2 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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 likely benign. 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 p.Thr935Met variant was identified in 4 of 32596 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, colorectal cancer or Lynch syndrome and was present in 1 of 11718 control chromosomes (frequency: 0.0001) from healthy individuals (Decker 2017, Pearlman 2017, Renwick 2006, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs3218708) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Color; and as uncertain significance by Invitae, Counsyl, GeneDx and one other submitter). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 15 of 277146 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), European in 13 of 126690 chromosomes (freq: 0.0001), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr935 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).