Submissions for variant NM_000051.4(ATM):c.4303A>C (p.Lys1435Gln)

dbSNP: rs876660964

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000216209	SCV000278826	uncertain significance	not provided	2023-07-31	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; Observed in individuals with breast and/or ovarian cancer (Singh et al., 2018); This variant is associated with the following publications: (PMID: 29470806, 35732320)
Ambry Genetics	RCV000562594	SCV000660606	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-11	criteria provided, single submitter	clinical testing	The p.K1435Q variant (also known as c.4303A>C), located in coding exon 28 of the ATM gene, results from an A to C substitution at nucleotide position 4303. The lysine at codon 1435 is replaced by glutamine, an amino acid with similar properties. This variant was observed in a study of 1010 unrelated Indian individuals diagnosed with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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.
Color Diagnostics, LLC DBA Color Health	RCV000562594	SCV000687537	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-12	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1435 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 been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704673	SCV000833630	uncertain significance	Ataxia-telangiectasia syndrome	2022-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1435 of the ATM protein (p.Lys1435Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 234267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM 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.
Natera, Inc.	RCV000704673	SCV001458204	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing