ClinVar Genomic variation as it relates to human health

The p.Y1961C variant (also known as c.5882A>G), located in coding exon 38 of the ATM gene, results from an A to G substitution at nucleotide position 5882. The tyrosine at codon 1961 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a patient with CLL and was shown to confer reduced, but not absent ATM kinase activity in in vitro studies (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has also been reported in breast and pancreatic cancer patients (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Chaffee KG et al. Genet. Med., 2018 01;20:119-127; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Germani A et al. J Clin Med, 2020 Sep;9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: ATM c.5882A>G (p.Tyr1961Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251076 control chromosomes, predominantly at a frequency of 7.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in multiple patients with CLL, breast cancer, or pancreatic cancer, without strong evidence supporting pathogenicity of this variant (Luo_1998, Austen_2005, Greenman_2007, Skowronska_2011, Grant_2015, Young_2015, Chaffee_2018, Girard_2019, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication lists the variant as having reduced ATM Kinase activity but does not provide data supporting this statement (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 16014569, 19431188, 28726808, 30303537, 25479140, 17344846, 9622061, 26837699, 21933854, 28652578, 31159747, 26787654). ClinVar contains an entry for this variant (Variation ID: 127413). Based on the evidence outlined above, the variant was classified as uncertain significance.

_x000D_ Criteria applied: PM2_SUP, PP3

a variant of uncertain significance in the ATM gene (p.Tyr1961Cys). This sequence change replaces tyrosine with cysteine at codon 1961 of the ATM protein (p.Tyr1961Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs56399311, gnomAD 0.004%). This variant has been observed in individuals affected with prostate cancer, pancreatic cancer, chronic lymphocytic leukemia, and T-cell lymphoblastic leukemia (PMID: 25479140, 9622061, 21933854, Invitae). However, in one of these individuals’ pathogenic alleles were also identified in ATM, which suggests that this c.5882A>G variant was not the primary cause of disease. ClinVar contains 9 entries for this variant (Variation ID: 127413), all of which interpreted this variant as of uncertain significance. This variant has been predicted as damaging by Polyphen and SIFT. 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.

This missense variant replaces tyrosine with cysteine at codon 1961 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the variant results in reduced ATM kinase activity in a cell line-based assay (PMID: 19431188). This variant has been reported in individuals affected with breast or pancreatic cancer (PMID: 25479140, 28726808, 28779002). In a large case-control study, this variant was reported in 5/60461 breast cancer cases and 2/53459 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). This variant has also been identified in 10/251076 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Observed in individuals with breast cancer, pancreatic cancer, prostate cancer, and various forms of leukemia (PMID: 21933854, 25479140, 28779002, 28726808, 32957588, 33436325, 35672297); Published functional studies suggest a damaging effect: reduced kinase activity (PMID: 19431188); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21933854, 22529920, 9622061, 16014569, 26787654, 27720647, 25479140, 28779002, 28726808, 25741868, 28652578, 17344846, 34426522, 32957588, 31159747, 30303537, 33436325, 35672297, 19431188, 26837699, 23532176, 34262154)

The ATM c.5882A>G (p.Tyr1961Cys) variant is considered likely pathogenic for hereditary cancer risk. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic ATM variants [PMID: 25085752]. However, at this time, it is unclear whether homozygous or compound heterozygous inheritance of this variant causes the recessive condition ataxia telangiectasia (AT).

The ATM c.5882A>G (p.Tyr1961Cys) variant has a classification of uncertain for Ataxia Telangiectasia (AT) as there is limited evidence regarding the association with this variant and AT in homozgyous or compound heterozygous individuals. However, this variant has been found to be associated with more severe personal and family histories of cancer and is therefore classified as likely pathogenic for hereditary cancer risk. Please note: this variant was assessed in the context of healthy population screening.