Submissions for variant NM_000051.4(ATM):c.5011G>T (p.Val1671Phe)

dbSNP: rs1057523385

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434309	SCV000531750	uncertain significance	not provided	2016-09-16	criteria provided, single submitter	clinical testing	The V1671F variant in the ATM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1671F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1671F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, and is not located in a known functional domain (Tavtigian et al., 2009; Stracker et al., 2013). In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V1671F as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817772	SCV000958355	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1671 of the ATM protein (p.Val1671Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 389279). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Genetic Services Laboratory, University of Chicago	RCV000434309	SCV002066795	likely pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with ATM-related disorders. This sequence change has not been described in the large population databases like ExAC and gnomAD (dbSNP rs1057523385). This sequence change is present in this individual's two children with ataxia telangiectasia along with another previously reported pathogenic variant in the ATM gene in the trans state (testing performed at an outside laboratory). The p.Val1671Phe change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1671Phe substitution. Given the above we classify this variant as Likely Pathogenic (ACMG/AMP criteria used: PM2, PM3, PP1, PP4)
Ambry Genetics	RCV002339077	SCV002641421	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	The p.V1671F variant (also known as c.5011G>T), located in coding exon 33 of the ATM gene, results from a G to T substitution at nucleotide position 5011. The valine at codon 1671 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well 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.