ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 799 of the ATM protein (p.Ala799Val). This variant is present in population databases (rs199954262, gnomAD 0.006%). This missense change has been observed in individual(s) with renal clear cell carcinoma (PMID: 25980754, 26689913, 31159747). ClinVar contains an entry for this variant (Variation ID: 181928). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Variant summary: ATM c.2396C>T (p.Ala799Val) 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 3.8e-05 in 316526 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (3.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2396C>T has been reported in the literature in individuals affected with Lynch syndrome-associated cancer and/or polyps and kidney renal clear cell carcinoma (Yurgelun_2015, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (ATM unspecified variant; MSH2 c.1576del, p.Thr526Profs*17; ATM, exons 61-62 deletion) (Yurgelun_2015, one clinical laboratory), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (4x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The ATM c.2396C>T (p.Ala799Val) missense change has a maximum frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108129732-C-T). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). This variant has been reported in an individual with renal clear cell carcinoma (PMID: 26689913), an individual with suspected Lynch syndrome (PMID: 25980754), an individual undergoing hereditary cancer syndrome testing (PMID: 31159747), and an unaffected individual (PMID: 30287823). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.

This variant is associated with the following publications: (PMID: 25980754, 26689913, 28779002, 31159747)

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.

The ATM p.Ala799Val variant was identified in 1 of 16622 proband chromosomes (frequency: 0.00006) from individuals or families with Lynch syndrome or breast cancer and was present in 4 of 22482 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs199954262) as "With Uncertain significance allele", ClinVar (classified as likely benign by GeneDx and Ambry Genetics; and as uncertain significance by Invitae and two other submitters), LOVD 3.0 (2x), and in 7 of 277034 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 7 of 126620 chromosomes (freq: 0.00006), but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala799 residue is not conserved in mammals and 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.