Submissions for variant NM_000051.4(ATM):c.5435C>T (p.Ala1812Val)

gnomAD frequency: 0.00001  dbSNP: rs199885813

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222750	SCV000273572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.A1812V variant (also known as c.5435C>T), located in coding exon 35 of the ATM gene, results from a C to T substitution at nucleotide position 5435. The alanine at codon 1812 is replaced by valine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected breast cancer patients and with an allele frequency of 0.00027 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000674622	SCV000799991	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674622	SCV000823241	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1812 of the ATM protein (p.Ala1812Val). This variant is present in population databases (rs199885813, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 28135145, 30287823). ClinVar contains an entry for this variant (Variation ID: 230134). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000222750	SCV000913958	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1812 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and colorectal cancer in the literature, but also in unaffected controls (PMID: 28135145, 30287823). This variant has been identified in 2/251084 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030596	SCV001193481	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Baylor Genetics	RCV004567515	SCV005053035	uncertain significance	Familial cancer of breast	2023-11-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000674622	SCV002081948	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-19	no assertion criteria provided	clinical testing