Submissions for variant NM_000051.4(ATM):c.3694T>C (p.Ser1232Pro)

gnomAD frequency: 0.00001  dbSNP: rs183532834

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000688001	SCV000815597	uncertain significance	Ataxia-telangiectasia syndrome	2023-05-04	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 567819). 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. 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. This missense change has been observed in individual(s) with unspecified cancer (PMID: 28873162). This variant is present in population databases (rs183532834, gnomAD 0.009%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1232 of the ATM protein (p.Ser1232Pro).
Fulgent Genetics, Fulgent Genetics	RCV000763699	SCV000894579	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777902	SCV000913925	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 1232 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/248336 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779057	SCV002015127	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3694T>C (p.Ser1232Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3694T>C has been reported in the literature in at least one individual affected with advanced cancer without clinical information or evidence of cosegregation (Mandelker_2017). The variant has been reported as a VUS in the Japanese population based on its occurrence in 2/11241 controls but not in 7051 breast cancer cases in women (e.g. Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002067000	SCV002496257	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Variant identified in individuals with advanced cancer and also in unaffected controls (Mandelker 2017, Momozawa 2018); This variant is associated with the following publications: (PMID: 28873162, 19781682, 30287823)
Sema4, Sema4	RCV000777902	SCV002536562	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
Ambry Genetics	RCV000777902	SCV002623979	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The p.S1232P variant (also known as c.3694T>C), located in coding exon 24 of the ATM gene, results from a T to C substitution at nucleotide position 3694. The serine at codon 1232 is replaced by proline, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients, though was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients or male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Baylor Genetics	RCV003472190	SCV004204289	uncertain significance	Familial cancer of breast	2023-10-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000688001	SCV002078925	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-25	no assertion criteria provided	clinical testing